9 Treatment of polymyalgia rheumatiea/giant cell arteritis VALERIE
KYLE
Corticosteroids are mandatory in the treatment of giant cell arteritis (GCA) because no other drug suppresses the arterial inflammation, thus preventing complications such as blindness and relieving symptoms rapidly and effectively. When corticosteroids were first used to treat GCA in the 1950s, the incidence of visual loss fell dramatically (Birkhead et al, 1957). In a series of 55 patients none developed bilateral blindness and only two unilateral blindness. In contrast, of 55 patients admitted for treatment before steroids were available, five presented with unilateral blindness which became bilateral, and eight patients developed unilateral blindness. Patients treated with corticosteroids were 'promptly relieved of their other symptoms' in almost all cases. The incidence of bilateral blindness fell from around 25% to 9%. Whitfield et al (1953) came to similar conclusions in an earlier report of GCA treated with cortisone and adrenocorticotrophic hormone (ACTH). Corticosteroids were equally effective in controlling symptoms in polymyalgia rheumatica (PMR): an early report states 'there was no doubt of the immediate response to these preparations' (Barber, 1957). The use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat PMR has been advocated (Goodman, 1975; Chuang et al, 1982) but, although partial relief of symptoms occurs, most physicians find steroids are necessary to achieve complete control of symptoms. American patients prescribed NSAIDs were able to stop treatment within months; the disease pattern may be different from that seen in Europe. The response to treatment is dramatic, with virtually complete relief of symptoms within 48-72 hours; a rapid response to prednisolone is included by many as one of the necessary criteria to make the diagnosis of PMR/GCA (Jones and Hazleman, 1981). The beneficial effects of treatment have to be balanced against the unwanted side-effects, and this is the major factor influencing the dose of prednisolone prescribed. The following aspects of corticosteroid therapy will be discussed: 1. 2.
Initial dose Rate of reduction
BailliOre's Clinical Rheumatology-Vol. 5, No. 3, December 1991 ISBN 0-7020-1537-7
485 Copyright 9 1991, by Bailli~re Tindall All rights of reproduction in any form reserved
486 3. 4.
V. KYLE
Duration of treatment Side-effects.
INITIAL PREDNISOLONE DOSE
Most studies report using 10-20 mg prednisolone/day for patients with PMR, although Bengtsson and Malmvall (1981a) used higher doses (mean 33 rag) because of concern over the potential development of arteritis. A minority have supported this viewpoint (Hamilton et al, 1971; Fauchald et al, 1972). GCA patients are usually treated with higher doses of prednisolone (40-60 mg/day), although some studies have reported success with 20 mg/day (Kogstad, 1965; Behn et al, 1983) and others, usually ophthalmologists, use higher doses such as 80mg/day (Wadman and Werner, 1972; Cohen and Hurd, 1981). In patients presenting with acute visual impairment, i.v. hydrocortisone or methylprednisolone has been used (Model, 1978; Graham et al, 1981). Treatment with alternate-day steroids has not proved effective (Bengtsson and Malmvall, 1981b). There are few prospective studies comparing initial corticosteroid doses. Kyle and Hazleman (1989a) compared high and low dose regimens over the first 2 months of treatment for 74 patients with GCA (39 PMR, 35 GCA) (Table 1). Thirteen of 20 patients taking the low dose regimen for PMR relapsed, six in the first month and seven in the second. Three of those relapses were due to the development of GCA, and two further patients developed GCA after relapsing. Only two of 19 patients taking the high dose regime relapsed, both at 6 weeks on 10 mg daily. Table 1. Steroid regimes mg/prednisolone per day for the first 2 months of treatment. PMR 4 weeks High Low
20 10
2 weeks 15 7.5
GCA 2 weeks
5 days
4 weeks
2 weeks
2 weeks
10 5
40 40
40 20
30 15
20 10
In the GCA group, all but two patients (one with arm claudication and one with persistent visual symptoms) were controlled on 40 mg/day for the first month, but dose reduction in the second month led to two further relapses. The low dose regimen for GCA (20 mg in the first month) did not control symptoms adequately; three patients relapsed in the first month and three in the second. Eight of the 10 GCA patients who relapsed also had symptoms of PMR. The high relapse rates on the lower dose regimens contrast with other studies (Myles, 1975; Mowat, 1979) but relapses were generally related to dose reduction in the second month or to the development of GCA, not to inadequate doses of prednisolone initially. It was concluded that 40 mg of prednisolone for GCA and 15 mg for prednisolone for PMR were appropriate initial treatment for most patients.
TREATMENT
487
A recent study (Catoggio et al, 1991) also emphasized the importance of gradual reduction of corticosteroid and found 10 mg/day of prednisolone adequate in PMR. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) usually fall to within normal levels within 1-2 weeks of starting prednisolone (Mallya et al, 1985; Kyle et al, 1989). RATE OF R E D U C T I O N OF CORTICOSTEROIDS
There is little information on the rate of corticosteroid reduction once initial symptoms are controlled. Weekly decrements of not more than 10% were suggested by Calamia and Hunder (1980) after an initial dose of 45-60 mg prednisolone daily. Another group reduced the prednisolone dose from 80 mg to 40 mg by 9 days, then by 5 mg/week until 10 mg daily was reached (Graham et al, 1981). Reducing prednisolone by i mg/month once the dose is stable has been proposed (Esselinckx et al, 1977). Retrospective studies of the mean daily prednisolone dose after 1-2 years report a dose range of 5-10 mg/day, usually with similar levels in PMR and GCA. At one year, ~70% were taking ___7.5mg (Bengtsson and Malmvall, 1981a). Ayoub et al (1985) found PMR patients were taking a mean of 8.1mg after 1 year of therapy. In a prospective study of 74 patients with PMR/GCA, we found the mean prednisolone dose at 1 year was 6-7.5 mg daily (Kyle and Hazleman, 1988). The incidence of relapse ranges from 4% to over 70%. Disease activity appears to decline steadily: relapses are most likely during the initial 18 months of treatment (Kyle and Hazleman, 1988) and within 1 year of withdrawal of corticosteroids (Behn et al, 1983). Relapses may occur after 10 years (Bengtsson and Malmvall, 1981a). There is no reliable method of predicting those most at risk: neither temporal artery biopsy results nor clinical or laboratory features at onset are helpful (Vilaseca et al, 1987; Delecoeuillerie et al, 1988). Arteritic relapses in patients who present with pure PMR are unusual (Spiera and Davison, 1982; Ayoub et al, 1985), although a study of general medical patients in hospital reported a high incidence of visual and neurological complications (Jones and Hazleman, 1981). Men were more likely than women to experience GCA complications in one study (Delecoeuillerie et al, 1988). Although it is well recognized that relapse, including loss of vision, can occur in patients who appear to be stable on an adequate dose of corticosteroids (Whitfield et al, 1963), most relapses are related to steroid reduction (Fauchald et al, 1972; Von Knorring, 1979). Rapid reduction or withdrawal of steroids has been reported to contribute to deaths in patients with GCA (Nordborg and Bengtsson, 1989). Thirteen of 17 deaths within 4 months of starting treatment were felt to be due to using an inadequate prednisolone dose or reducing the dose too rapidly. The ESR or CRP may be elevated in 70-100% of relapses (Eshagian and Goeken, 1981; Hickling et al, 1986), but we have found that clinical relapse with normal ESR or CRP occurred in about half the patients (Kyle et al,
488
v. KYLE
1989). Alterations in treatment should be based on the clinical picture rather than laboratory tests. LENGTH OF TREATMENT Most studies report that treatment is needed for at least 2 years. Fauchald et al (1972) found only 14% of 94 PMR/GCA patients had managed to stop steroids at 16 months, and Myles (1975) reported similar results: 17% off at 21 months with more than one-third of 84 PMR/GCA patients still taking steroids after 4 years. Another group found 84% of patients remained on steroids at 5 years (Coomes et al, 1976). More recent studies report a similar pattern. Ninety PMR/GCA patients were followed for 3-10 years: 37 had discontinued steroids at a mean of 27 months, but 35 still needed treatment at a mean of 59 months (Bengtsson and Malmvall, 1981a). In a series of GCA patients with predominantly visual or neurological problems, onethird were found to require treatment indefinitely (Graham et al, 1981). Behn et al (1983) found 72 of 176 patients had discontinued treatment at a mean of 31 months. One group performed lifetable analysis and found 40% of PMR patients were likely to need treatment at 4 years (Ayoub et al, 1985). A recent French study (Delecoeuillerie et al, 1988) reported that 65 of 132 PMR patients had stopped steroids after a mean of 25.7 months, and 40 of 78 GCA patients at 30.9 months. A prospective study (Kyle and Hazleman, 1988) found 24% of PMR/GCA patients were able to stop steroids by 2 years. In contrast, USA studies report a much shorter disease duration for both PMR and GCA (Huston and Hunder, 1980; Chuang et al, 1982): 11 months was the median duration of treatment for PMR and most patients with both PMR and GCA stopped steroids within 2 years. There are problems in interpreting these studies with respect to individual patients. Some groups included PMR and GCA, some only biopsy-positive GCA cases, and most studies were retrospective. However, the consensus view appears to be that stopping treatment from 2 years onwards is feasible. There is recent laboratory evidence to support this. Dasgupta et al (1989) measured serum T-cell subsets before and during treatment in PMR/GCA and found a profound and selective reduction of suppressor cytotoxic cells which persisted for up to 1 year despite satisfactory disease control in terms of symptoms, ESR and CRP. After 2 years of treatment the levels of CD8+ return to those found in normal controls. Monitoring CD8+ levels may prove useful in predicting when steroids can be withdrawn. However, other groups did not reach the same conclusions on the relationship between decreased CD8+ cells and disease activity or duration (Benlahrache et al, 1983; Elling and Elling, 1985). The relapse rate after withdrawal of steroids ranges from 4 to 43%. Patients usually relapse within 1 year of stopping prednisolone but late relapses occasionally occur (Bengtsson and Malmvall, 1981a). In patients where reduction or withdrawal of steroids is difficult, azathioprine has a modest steroid-sparing effect (de Silva and Hazleman,
TREATMENT
489
1986). The addition of a NSAID may ease the 'pseudorheumatism' which occurs in some patients trying to wean themselves from low dose prednisolone (less than 5 mg). Very gradual reduction, for example reducing the dose by 1 mg on alternate days, may help. There is a report of the value of methotrexate in three 'steroid-resistant' cases o f P M R / G C A , but one patient had an overlap connective tissue disease and one was probably inadequately treated initially (Krall et al, 1989). CORTICOSTEROID-RELATED SIDE-EFFECTS
Patients are at risk of the usual side-effects such as osteoporosis, infection, cataract, diabetes mellitus, hypertension, weight gain and skin fragility. The reported incidence of side-effects ranges from 20 to 50% (Von Knorring, 1979; Fainaru et al, 1979) but the incidence is much lower if the prednisolone dose is 10rag or less initially, with maintenance doses of 7.5rag or less (Coomes et al, 1976; Spiera and Davison, 1982; Kyle and Hazleman, 1989b). High initial cumulative and maintenance doses of prednisolone have all been linked to a higher incidence of side-effects. A recent study suggested that the incidence of osteoporosis was not increased in GCA patients treated with steroids, but quantitative measurements of the bone mineral density were not used (Andersson et al, 1990). Studies need to be done assessing the use of prophylactic treatment to reduce the development of osteoporosis and fracture. SUMMARY
Corticosteroids control arteritis in GCA and suppress polymyalgicsymptoms within days of starting treatment. PMR patients can be treated with approximately 15 mg prednisolone/day, reducing the dose to 7.5-10 mg by 8 weeks. GCA is normally controlled on 40 mg prednisolone/day, although patients with persistent visual symptoms may need 60-80 rag. Slow reduction to about 20 mg by 8 weeks should minimize relapses. For both PMR and GCA a maintenance dose of 7.5rag after 6-9 months should be enough. Steroid withdrawal is possible within 2 years of starting treatment, although some will need 4 years or more. Relapse should be defined clinically; the ESR is the most useful laboratory parameter. Steroid side-effects can be minimized by using low doses of prednisolone whenever possible and azathioprine may be used as a steroid-sparing agent.
REFERENCES
Andersson R, RundgrenA, RosengrenK et al (1990) Osteoporosisafter longterm corticosteroid treatmentof giantcell arteritis. Journal of Internal Medicine 227: 391-395. Ayoub WT, FranklinCM & Torretti D (1985) Polymyalgiarheumatica.Durationof therapy and long term outcome.American Journal of Medicine 79: 309-315.
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V. KYLE
Barber HS (1957) Myalgic syndrome with constitutional effects. Polymyalgia rheumatica. Annals of the Rheumatic Diseases 16: 230-237. Behn AR, Perera T & Myles AB (1983) Polymyalgia rheumatica and corticosteroids: how much for how long? Annals of the Rheumatic Diseases 42: 374-378. Bengtsson BE & Malmvall BA (1981a) Prognosis of giant cell arteritis including temporal arteritis and polymyalgia rheumatica. Acta Medica Scandinavica 209: 337-345. Bengtsson BA & Malmvall BE (1981b) An alternate day corticosteroid regimen in maintenance therapy of giant cell arteritis. Acta Medica Scandinavica 209: 347-350. Benlahrache C, Segond P, Aquier L & Bouvet JP (1983) Decrease of the OKT8-positive T cell subset in polymyalgia rheumatica. Lack of correlation with disease activity. Arthritis and 9 Rheumatism 26: 1472-1479. Birkhead NC, Wagener HP & Shick RM (1957) Treatment of temporal arteritis with adrenal corticosteroids. Journal of the American Medical Association 163: 821-827. Calamia KT & Hunder GG (1980) Clinical manifestation of giant cell (temporal) arteritis. Clinics in Rheumatic Diseases 6: 389-403. Catoggio L J, Soriano ER & Imamura PM (1991) Treatment of polymyalgia rheumatica: lower initial dose. British Journal of Rheumatology 30:395 (letter). Chuang T-Y, Hunder GG, Ilstrup DM & Kurland LT (1982) Polymyalgia rheumatica. A 10 year epidemiological and clinical study. Annals oflnternal Medicine 97: 672-680. Cohen MD & Hurd ER (1981) Neurological complications of connective tissue and other 'collagen vascular' diseases. Seminars in Arthritis and Rheumatism 11: 190-212. Coomes EN, Ellis RM & Kay AG (1976) A prospective study of 102 patients with polymyalgia rheumatica syndrome. Rheumatology and Rehabilitation Dasgupta B, Duke O, Timms AM, Pitzalis C & Panayi GS (1989) Selective depletion and activation of CD8+ lymphocytes from peripheral blood of patients with polymyalgia rheumatica and giant cell arteritis. Annals of the Rheumatic Diseases 48: 307-311. Delecoeuillerie D, Jolly P, Cohen de Lara A & Paolaggi JB (1988) Polymyalgia rheumatica and temporal arteritis: a retrospective analysis of prognostic factors and different corticosteroid regimes (11 year survey of 210 patients). Annals of the Rheumatic Diseases 47: 733-739. Elling H & Elling P (1985) Decreased level of suppressor-cytotoxic T cells (OKTSa) in polymyalgia rheumatica and giant cell arteritis. Journal of Rheumatology 12: 306309. Eshagian J & Goeken JA (1980) C-reactive protein in giant cell (cranial, temporal) arteritis. Ophthalmology 87: 1160-1166. Esselinckx W, Doherty SM & Dixon AStJ (1977) Polymyalgia rheumatica. Abrupt and gradual withdrawal of prednisolone treatment, clinical and laboratory observations. Annals of the Rheumatic Diseases 36: 219-224. Fainaru M, Friedman G & Friedman B (1979) Temporal arteritis in Israel. A review of 47 patients. Journal of Rheumatology 6: 330-335. Fauchald R, Rygold O & Oystese B (1972) Temporal arteritis and polymyalgia rheumatica. Clinical and biopsy findings. Annals oflnternal Medicine 77: 845-852. Goodman BJ (1979) Temporal arteritis. American Journal of Medicine 67: 839-852. Graham E, Holland A, Avery A & Russell RWR (1981) Prognosis in giant cell arteritis. British Medical Journal 292: 269-271. Hamilton CR, Shelley WM, Tumulty PA (1971) Giant cell arteritis: including temporal arteritis and polymyalgia rhenmatica. Medicine (Baltimore) 50: 1-27. Hickling P, Dixon JS, Bird HA et al (1986) Acute phase reactions as predictors of the success of steroid withdrawal in polymyalgia rheumatica. British Journal of Rheumatology 25:98 (abstract no. 23). Hunder GG, Sheps SG, Allen GL & Joyce JW (1975) Daily and alternate day corticosteroid regimens in treatment of giant cell arteritis. Comparison in a prospective study. Annals of Internal Medicine 82: 613-618. Huston KA & Hunder GG (1980) Giant cell arteritis: a clinical review. American Heart Journal 100: 99-107. Jones JG & Hazleman BL (1981) Prognosis and management of potymyalgia rheumatica. Annals o f the Rheumatic Diseases 40: 1-5. Kogstad OA (1965) Polymyalgia rheumatica and its relation to arteritis temporalis. Acta Medica Scandinavica 178: 591-598.
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Krall PL, Mazanec DJ & Wilkie WS (1989) Methotrexate for corticosteroid resistant polymyalgia rheumatica and giant cell arteritis. Cleveland Clinic Journal o f Medicine 56: 253-257. Kyle V & Hazleman BL (1988) The clinical and laboratory course of polymyalgia rheumatica/ giant cell arteritis. British Journal o f Rheumatology 27 (supplement 1): 7. Kyle V & Hazleman BL (1989a) Treatment of polymyalgia rheumatica and giant cell arteritis. I. Steroid regimes in the first two months. Annals o f the Rheumatic Diseases 48: 658-661. Kyle V & Hazleman BL (1989b) Treatment of polymyalgia rheumatica and giant cell arteritis. II. The relationship between steroid dose and steroid-associated side effects. Annals o f the Rheumatic Diseases 48: 662-666. Kyle V, Cawston TE & Hazleman BL (1989) Erythrocyte sedimentation rate and cREACTIVE protein in the assessment of polymyalgia rheumatica/giant cell arteritis on presentation and during follow up. Annals o f the Rheumatic Diseases 48: 667-671. Mallya RK, Hind CRK, Berry H & Pepys MB (1985) Serum C-reactive protein in polymyalgia rheumatica: a prospective serial study. Arthritis and Rheumatism 28: 383-387. Model DG (1978) Reversal of blindness in temporal arteritis with methyl prednisolone. Lancet i: 340. Mowat AG (1979) Generalised rheumatism: polymyalgia rheumatica and its different diagnosis. Clinics in Rheumatic Diseases 5: 775-795. Myles AB (1975) Polymyalgia rheumatica and giant cell arteritis. Rheumatology and Rehabilitation 14: 3231-3235. Nordborg E & Bengtsson BA (1989) Death rates and causes of death in 284 consecutive patients with giant cell arteritis confirmed by biopsy. British Medical Journal 229: 549-550. Spiera H & Davison S (1982) Treatment of polymyalgia rheumatica. Arthritis and Rheumatism 25: 120. Vilaseca J, Gonzales A, Cid MC, Lopez-Vivancos J & Ortega A (1987) Clinical usefulness of temporal artery biopsy. Annals o f the Rheumatic Diseases 46: 282-285. Von Knorring J (1979) Treatment and prognosis in polymyalgia rheumatica and giant cell arteritis. Acta Medica Scandinavica 205: 429-435. Wadman B & Werner I (1972) Observations on temporal arteritis. Acta Medica Scandinavica 192: 377-383. Whitfield AGW, Cooke WT, Jameson-Evans P & Rudd C (1953) Temporal arteritis and its treatment with cortisone and ACTH. Lancet i: 408-412. Whitfield A G W , Bateman M & Cooke WT (1963) Temporal arteritis. British Journal of Ophthalmology 47: 555-566.
KYLE
Corticosteroids are mandatory in the treatment of giant cell arteritis (GCA) because no other drug suppresses the arterial inflammation, thus preventing complications such as blindness and relieving symptoms rapidly and effectively. When corticosteroids were first used to treat GCA in the 1950s, the incidence of visual loss fell dramatically (Birkhead et al, 1957). In a series of 55 patients none developed bilateral blindness and only two unilateral blindness. In contrast, of 55 patients admitted for treatment before steroids were available, five presented with unilateral blindness which became bilateral, and eight patients developed unilateral blindness. Patients treated with corticosteroids were 'promptly relieved of their other symptoms' in almost all cases. The incidence of bilateral blindness fell from around 25% to 9%. Whitfield et al (1953) came to similar conclusions in an earlier report of GCA treated with cortisone and adrenocorticotrophic hormone (ACTH). Corticosteroids were equally effective in controlling symptoms in polymyalgia rheumatica (PMR): an early report states 'there was no doubt of the immediate response to these preparations' (Barber, 1957). The use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat PMR has been advocated (Goodman, 1975; Chuang et al, 1982) but, although partial relief of symptoms occurs, most physicians find steroids are necessary to achieve complete control of symptoms. American patients prescribed NSAIDs were able to stop treatment within months; the disease pattern may be different from that seen in Europe. The response to treatment is dramatic, with virtually complete relief of symptoms within 48-72 hours; a rapid response to prednisolone is included by many as one of the necessary criteria to make the diagnosis of PMR/GCA (Jones and Hazleman, 1981). The beneficial effects of treatment have to be balanced against the unwanted side-effects, and this is the major factor influencing the dose of prednisolone prescribed. The following aspects of corticosteroid therapy will be discussed: 1. 2.
Initial dose Rate of reduction
BailliOre's Clinical Rheumatology-Vol. 5, No. 3, December 1991 ISBN 0-7020-1537-7
485 Copyright 9 1991, by Bailli~re Tindall All rights of reproduction in any form reserved
486 3. 4.
V. KYLE
Duration of treatment Side-effects.
INITIAL PREDNISOLONE DOSE
Most studies report using 10-20 mg prednisolone/day for patients with PMR, although Bengtsson and Malmvall (1981a) used higher doses (mean 33 rag) because of concern over the potential development of arteritis. A minority have supported this viewpoint (Hamilton et al, 1971; Fauchald et al, 1972). GCA patients are usually treated with higher doses of prednisolone (40-60 mg/day), although some studies have reported success with 20 mg/day (Kogstad, 1965; Behn et al, 1983) and others, usually ophthalmologists, use higher doses such as 80mg/day (Wadman and Werner, 1972; Cohen and Hurd, 1981). In patients presenting with acute visual impairment, i.v. hydrocortisone or methylprednisolone has been used (Model, 1978; Graham et al, 1981). Treatment with alternate-day steroids has not proved effective (Bengtsson and Malmvall, 1981b). There are few prospective studies comparing initial corticosteroid doses. Kyle and Hazleman (1989a) compared high and low dose regimens over the first 2 months of treatment for 74 patients with GCA (39 PMR, 35 GCA) (Table 1). Thirteen of 20 patients taking the low dose regimen for PMR relapsed, six in the first month and seven in the second. Three of those relapses were due to the development of GCA, and two further patients developed GCA after relapsing. Only two of 19 patients taking the high dose regime relapsed, both at 6 weeks on 10 mg daily. Table 1. Steroid regimes mg/prednisolone per day for the first 2 months of treatment. PMR 4 weeks High Low
20 10
2 weeks 15 7.5
GCA 2 weeks
5 days
4 weeks
2 weeks
2 weeks
10 5
40 40
40 20
30 15
20 10
In the GCA group, all but two patients (one with arm claudication and one with persistent visual symptoms) were controlled on 40 mg/day for the first month, but dose reduction in the second month led to two further relapses. The low dose regimen for GCA (20 mg in the first month) did not control symptoms adequately; three patients relapsed in the first month and three in the second. Eight of the 10 GCA patients who relapsed also had symptoms of PMR. The high relapse rates on the lower dose regimens contrast with other studies (Myles, 1975; Mowat, 1979) but relapses were generally related to dose reduction in the second month or to the development of GCA, not to inadequate doses of prednisolone initially. It was concluded that 40 mg of prednisolone for GCA and 15 mg for prednisolone for PMR were appropriate initial treatment for most patients.
TREATMENT
487
A recent study (Catoggio et al, 1991) also emphasized the importance of gradual reduction of corticosteroid and found 10 mg/day of prednisolone adequate in PMR. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) usually fall to within normal levels within 1-2 weeks of starting prednisolone (Mallya et al, 1985; Kyle et al, 1989). RATE OF R E D U C T I O N OF CORTICOSTEROIDS
There is little information on the rate of corticosteroid reduction once initial symptoms are controlled. Weekly decrements of not more than 10% were suggested by Calamia and Hunder (1980) after an initial dose of 45-60 mg prednisolone daily. Another group reduced the prednisolone dose from 80 mg to 40 mg by 9 days, then by 5 mg/week until 10 mg daily was reached (Graham et al, 1981). Reducing prednisolone by i mg/month once the dose is stable has been proposed (Esselinckx et al, 1977). Retrospective studies of the mean daily prednisolone dose after 1-2 years report a dose range of 5-10 mg/day, usually with similar levels in PMR and GCA. At one year, ~70% were taking ___7.5mg (Bengtsson and Malmvall, 1981a). Ayoub et al (1985) found PMR patients were taking a mean of 8.1mg after 1 year of therapy. In a prospective study of 74 patients with PMR/GCA, we found the mean prednisolone dose at 1 year was 6-7.5 mg daily (Kyle and Hazleman, 1988). The incidence of relapse ranges from 4% to over 70%. Disease activity appears to decline steadily: relapses are most likely during the initial 18 months of treatment (Kyle and Hazleman, 1988) and within 1 year of withdrawal of corticosteroids (Behn et al, 1983). Relapses may occur after 10 years (Bengtsson and Malmvall, 1981a). There is no reliable method of predicting those most at risk: neither temporal artery biopsy results nor clinical or laboratory features at onset are helpful (Vilaseca et al, 1987; Delecoeuillerie et al, 1988). Arteritic relapses in patients who present with pure PMR are unusual (Spiera and Davison, 1982; Ayoub et al, 1985), although a study of general medical patients in hospital reported a high incidence of visual and neurological complications (Jones and Hazleman, 1981). Men were more likely than women to experience GCA complications in one study (Delecoeuillerie et al, 1988). Although it is well recognized that relapse, including loss of vision, can occur in patients who appear to be stable on an adequate dose of corticosteroids (Whitfield et al, 1963), most relapses are related to steroid reduction (Fauchald et al, 1972; Von Knorring, 1979). Rapid reduction or withdrawal of steroids has been reported to contribute to deaths in patients with GCA (Nordborg and Bengtsson, 1989). Thirteen of 17 deaths within 4 months of starting treatment were felt to be due to using an inadequate prednisolone dose or reducing the dose too rapidly. The ESR or CRP may be elevated in 70-100% of relapses (Eshagian and Goeken, 1981; Hickling et al, 1986), but we have found that clinical relapse with normal ESR or CRP occurred in about half the patients (Kyle et al,
488
v. KYLE
1989). Alterations in treatment should be based on the clinical picture rather than laboratory tests. LENGTH OF TREATMENT Most studies report that treatment is needed for at least 2 years. Fauchald et al (1972) found only 14% of 94 PMR/GCA patients had managed to stop steroids at 16 months, and Myles (1975) reported similar results: 17% off at 21 months with more than one-third of 84 PMR/GCA patients still taking steroids after 4 years. Another group found 84% of patients remained on steroids at 5 years (Coomes et al, 1976). More recent studies report a similar pattern. Ninety PMR/GCA patients were followed for 3-10 years: 37 had discontinued steroids at a mean of 27 months, but 35 still needed treatment at a mean of 59 months (Bengtsson and Malmvall, 1981a). In a series of GCA patients with predominantly visual or neurological problems, onethird were found to require treatment indefinitely (Graham et al, 1981). Behn et al (1983) found 72 of 176 patients had discontinued treatment at a mean of 31 months. One group performed lifetable analysis and found 40% of PMR patients were likely to need treatment at 4 years (Ayoub et al, 1985). A recent French study (Delecoeuillerie et al, 1988) reported that 65 of 132 PMR patients had stopped steroids after a mean of 25.7 months, and 40 of 78 GCA patients at 30.9 months. A prospective study (Kyle and Hazleman, 1988) found 24% of PMR/GCA patients were able to stop steroids by 2 years. In contrast, USA studies report a much shorter disease duration for both PMR and GCA (Huston and Hunder, 1980; Chuang et al, 1982): 11 months was the median duration of treatment for PMR and most patients with both PMR and GCA stopped steroids within 2 years. There are problems in interpreting these studies with respect to individual patients. Some groups included PMR and GCA, some only biopsy-positive GCA cases, and most studies were retrospective. However, the consensus view appears to be that stopping treatment from 2 years onwards is feasible. There is recent laboratory evidence to support this. Dasgupta et al (1989) measured serum T-cell subsets before and during treatment in PMR/GCA and found a profound and selective reduction of suppressor cytotoxic cells which persisted for up to 1 year despite satisfactory disease control in terms of symptoms, ESR and CRP. After 2 years of treatment the levels of CD8+ return to those found in normal controls. Monitoring CD8+ levels may prove useful in predicting when steroids can be withdrawn. However, other groups did not reach the same conclusions on the relationship between decreased CD8+ cells and disease activity or duration (Benlahrache et al, 1983; Elling and Elling, 1985). The relapse rate after withdrawal of steroids ranges from 4 to 43%. Patients usually relapse within 1 year of stopping prednisolone but late relapses occasionally occur (Bengtsson and Malmvall, 1981a). In patients where reduction or withdrawal of steroids is difficult, azathioprine has a modest steroid-sparing effect (de Silva and Hazleman,
TREATMENT
489
1986). The addition of a NSAID may ease the 'pseudorheumatism' which occurs in some patients trying to wean themselves from low dose prednisolone (less than 5 mg). Very gradual reduction, for example reducing the dose by 1 mg on alternate days, may help. There is a report of the value of methotrexate in three 'steroid-resistant' cases o f P M R / G C A , but one patient had an overlap connective tissue disease and one was probably inadequately treated initially (Krall et al, 1989). CORTICOSTEROID-RELATED SIDE-EFFECTS
Patients are at risk of the usual side-effects such as osteoporosis, infection, cataract, diabetes mellitus, hypertension, weight gain and skin fragility. The reported incidence of side-effects ranges from 20 to 50% (Von Knorring, 1979; Fainaru et al, 1979) but the incidence is much lower if the prednisolone dose is 10rag or less initially, with maintenance doses of 7.5rag or less (Coomes et al, 1976; Spiera and Davison, 1982; Kyle and Hazleman, 1989b). High initial cumulative and maintenance doses of prednisolone have all been linked to a higher incidence of side-effects. A recent study suggested that the incidence of osteoporosis was not increased in GCA patients treated with steroids, but quantitative measurements of the bone mineral density were not used (Andersson et al, 1990). Studies need to be done assessing the use of prophylactic treatment to reduce the development of osteoporosis and fracture. SUMMARY
Corticosteroids control arteritis in GCA and suppress polymyalgicsymptoms within days of starting treatment. PMR patients can be treated with approximately 15 mg prednisolone/day, reducing the dose to 7.5-10 mg by 8 weeks. GCA is normally controlled on 40 mg prednisolone/day, although patients with persistent visual symptoms may need 60-80 rag. Slow reduction to about 20 mg by 8 weeks should minimize relapses. For both PMR and GCA a maintenance dose of 7.5rag after 6-9 months should be enough. Steroid withdrawal is possible within 2 years of starting treatment, although some will need 4 years or more. Relapse should be defined clinically; the ESR is the most useful laboratory parameter. Steroid side-effects can be minimized by using low doses of prednisolone whenever possible and azathioprine may be used as a steroid-sparing agent.
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