19
EDITORIALS
unknown and will settle for an old friend even if there is associated toxicity. Perhaps this is why gold (an expensive, dangerous, and often ineffective drug) still has so many proponents. Double-blind, controlled small studies substantiate its beneficial effect, but what do we learn from population-based community studies? An advantage of such investigations is that the findings relate to "real-life": the constraints of a formal study in an academic unit are avoided and patient selection is empirical rather than determined
by artificial selection criteria. Epstein and colleagues from San Francisco1O conducted a five-year prospective observational surveillance study of intramuscular gold and concluded that "on average, no statistically significant change in function or number of painful joints" occurred between 1983 and Gold therapy in rheumatoid arthritis Over 60 years ago Forrestier introduced gold for the management of rheumatoid arthritis (RA).1 His premise was that the disease was related to tuberculosis and that gold salts had an antitubercular effect. Thereafter, confidence in this heavy metal waxed and waned, finally becoming established when the Empire Rheumatism Council concluded from a multicentre controlled trial2,3that intramuscular gold was efficacious in RA. In 1974, Sigler et al4 reported that gold decreased the rate of disease progression as assessed with radiographs, and further controlled studies substantiated the clinical role of the intramuscular preparation by comparison with placebo, oral gold (’Auranofm’), and sulphasalazine.5,6 Nevertheless, there are serious drawbacks to such therapy-lack of efficacy in some patients, toxicity in many, and generally low continuation rates. Some researchers7,8have questioned whether gold really modifies disease at all. In addition, frequent
laboratory tests are required, injections are unpleasant, and there are many alternatives, ranging from the oral gold preparation to the increasingly popular methotrexate and sulphasalazine. In 1977 it was suggested that gold therapy had no role in modem medicine;9 and, with the advent of penicillamine and later methotrexate, this view evoked some sympathy. The picture is as unclear now as it was then. New molecules roll off the production lines almost monthly, but the optimism of clinicians is tinged with increasing cynicism. Should one give monoclonal antibodies directed against CD4, CD5, CD7, or other epitopes or would it be preferable to inhibit angiogenesis or metalloproteins? Maybe antiDR4, macrophage antibodies, soluble T-cell receptors, or T-cell vaccinations would be best. Possibly several drugs should be given in combination; if so, should one choose A--+A + B--+A + B + C, or A+B+C->A+B-->A? It is difficult to decide whether any of these exciting new developments will be good or bad for arthritis or good or bad for the patient. Many doctors fear the
1988. These researchers also noted that the outcome in patients who had received the gold for at least two consecutive years and in those who had not received such therapy was not statistically different. Epstein had previously suggested that there was no place for gold in modem rheumatology.Should one accept these data as being more relevant than those of double-blind controlled trials? Population-based studies have several shortcomings. First, they take no note of the subset of individuals who have done especially well (or badly). Second, without a placebo arm one has to accept that, had no treatment been given, the gold cohort might have fared less well than the non-gold cohort. Third, those not receiving gold may well have received other adequate therapies. These and other confounding variables make it difficult to draw a conclusion from such a study. One can be confident that rheumatologists who favour the use of gold, because of the dramatic improvement in a few patients, will continue to use it, whereas those who have little enthusiasm for the drug will be comforted by this latest report. There is little chance that clinicians’ behaviour will change. Corkill et all1 lately reported the advantages of induction therapy with depot methylprednisolone in conjunction with chrysotherapy-an approach that may enhance efficacy while decreasing toxicity. Such work rekindles interest in both gold and steroids. Lehtinen and Isomakil2 in Finland, in a study of 573 patients, found that gold treatment seemed to prevent premature death in RA, although their hypothesis had been the reverse. Irrespective of the results from many conflicting studies of diverse design, the fact remains that no more than 20% of patients who embark on parenteral gold therapy will still be receiving the drug after a five-year follow-up period, so any positive attributes of gold must be short lived. 1. Fifty years of gold in rheumatoid arthritis. Br Med J 1979; i: 289-90. 2. Research Sub-Committee of the Empire Rheumatism Council. Gold therapy in rheumatoid arthritis: report of a multi-centre controlled trial. Ann Rheum Dis 1960; 19: 95-119. 3. Research Sub-Committee of the Empire Rheumatism Council. Gold therapy in rheumatoid arthritis. Ann Rheum Dis 1961; 20: 315-40. 4. Sigler JW, Bluhm GM, Duncan H, Sharp JT, Ensign DC, McCrum WR. Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 1974; 80: 21-26.
20
syndrome and Miesher’s cheilitis granulomatosa. Melkersson-Rosenthal syndrome is primarily a triad of fissured tongue, facial or labial swelling, and facial palsy but there may be other lesions." Some patients with this syndrome have allergic symptoms,13 slightly raised serum immunoglobulin concentrations, and a raised erythrocyte sedimentation rate.13 The suggestion14
Crohn’s disease). Nevertheless, only very few patients with Melkersson-Rosenthal syndrome have manifested sarcoidosis or Crohn’s disease. 18 Miescher’s granulomatous cheilitis is characterised by isolated labial swelling, and is probably an oligosymptomatic form of Melkersson-Rosenthal syndrome.13 A very few patients have had or have progressed to Crohn’s disease, but again most do not. Thus it is clear that orofacial lesions with noncaseating granulomas on biopsy specimens may arise in the absence of any evidence of intestinal Crohn’s disease. The aetiology of these conditions is unclear, but some appear to be idiosyncratic responses to defmed food constituents or additives or to other exogenous factors. Management should include biopsy of the lesion and exclusion of intestinal Crohn’s disease by haematological and biochemical investigations; if there are abdominal symptoms, bowel radiography and possibly biopsy are indicated. Histological features of oral biopsy specimens in Crohn’s disease and in orofacial granulomatosis are essentially identical. There is oedema of the superficial corium with lymphangiectasia, and both diffuse and focal aggregates of small lymphocytes. In longstanding lesions there may be irregular fibrosis. Non-caseating epithelioid granulomas with or without multinucleated giant cells may be present but are often poorly formed and patchily distributed. Aggregates of mononuclear cells or frank granulomas can sometimes be seen bulging into or blocking lymphatic vessels. Occasionally there is ulceration of the overlying epithelium. Sarcoid granulomas are typically well-formed and discrete or confluent and are usually readily distinguishable from those of orofacial granulomatosis. For gingival lesions the distinction is much harder because of the dense inflammatory overlay. It may therefore be necessary to exclude sarcoidosis by chest radiography, serum angiotensin-converting enzyme measurements, and possibly a Kveim test. The outlook for patients with orofacial granulomatosis is variable and treatment is often unrewarding. Occasionally the condition remits spontaneously, especially in younger individuals.6,19 Some patients have only mild features and require no treatment, although tooth-associated infections should be eliminated.B Facial swelling, oral ulceration, or other lesions will necessitate therapy; a few of these abnormalities resolve with elimination diets but others may require topical, systemic, or intralesional corticosteroids.6,8,13 Danazol may be helpfupo and clofazimine has been effective, at least in Miescher’s granulomatous cheilitis.21 Hydroxychloroquine benefited one patient with Miescher’s cheilitis.22 Salazosulphapyridine, co-
that the condition is a variant of sarcoidosis has not been confirmed,ls although occasional patients have a positive Kveim reaction16 or raised serum angiotensin-converting enzyme concentrations17 (the Kveim reaction is occasionally positive in classic
trimoxazole, metronidazole, azathioprine, or cyclosporin have had little beneficial effect in the few patients in whom they have been tried.6,8,13 Surgical reduction of the facial swelling is probably not warranted or reliably effective.13
5. Ward JR, Williams HJ, Egger MJ, et al. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1983; 26: 1303-15. 6. Williams HJ, Ward JR, Dahl SL, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum 1988; 31: 703-13. 7. Kushner I. Does aggressive therapy of rheumatoid arthritis affect outcome? J Rheumatol 1989; 16: 104. 8. Epstein WV. Parenteral gold therapy for rheumatoid arthritis: a treatment whose time has gone. J Rheumatol 1989; 16: 1291-94. 9. Editorial. Gold therapy in 1975. Br Med J 1975; ii: 156-57. 10. Epstein WV, Henke CJ, Yelin EH, Katz PP. Effect of parenterally administered gold therapy on the course of adult rheumatoid arthritis. Ann Intern Med 1991; 114: 437-44. 11. Corkill MM, Kirkham BW, Chikanza IC, Gibson T, Panayi GS. Intramuscular depot methylprednisolone induction of chrysotherapy in rheumatoid arthritis: a 24-week randomized controlled trial. Br J Rheumatol 1990; 29: 274-79. 12. Lehtinen K, Isomaki H. Intramuscular gold therapy is associated with long survival in patients with rheumatoid arthritis. J Rheumatol 1991; 18: 524-29.
Orofacial
granulomatosis
Oral lesions are common in patients with proven Crohn’s disease of the intestine and include aphthae,l,2 diffuse swellings of the cheeks or lips,2 chronic inflammatory hyperplasia with fissuring and a cobblestone appearance of the mucosa,3mucosal tags,22 vertical fissures in the lips,4 and hyperplastic gingivitis.S These lesions may antedate bowel symptoms, often by several years,and may be the only obvious site of disease.Some patients with oral lesions-between 10% and 48% in various serieshave symptomless intestinal disease.8 Wiesenfeld et al8 have introduced the term orofacial granulomatosis for lesions that resemble those of Crohn’s disease clinically and histologically in patients who do
have accompanying gastrointestinal abnormalities, on the grounds that non-caseating granulomas are often seen in biopsy specimens. A familial pattern has been recognised in some cases of orofacial granulomatosis9 but not all.8 Between 12% and 60% of patients are atopic, and a few patients seem to have specific intolerances to foods or not
additives-eg, cinnamaldehyde, carvone, peperitone, cocoa, carmosine, sun yellow, or monosodium glutamate"—or to materials such as cobalt. 12 The distinction between orofacial granulomatosis with other conditions and non-caseating granulomas--eg, oral Crohn’s disease-may not be easy. Orofacial granulomatosis may be part of a spectrum of disorders that includes MelkerssonRosenthal
EDITORIALS
unknown and will settle for an old friend even if there is associated toxicity. Perhaps this is why gold (an expensive, dangerous, and often ineffective drug) still has so many proponents. Double-blind, controlled small studies substantiate its beneficial effect, but what do we learn from population-based community studies? An advantage of such investigations is that the findings relate to "real-life": the constraints of a formal study in an academic unit are avoided and patient selection is empirical rather than determined
by artificial selection criteria. Epstein and colleagues from San Francisco1O conducted a five-year prospective observational surveillance study of intramuscular gold and concluded that "on average, no statistically significant change in function or number of painful joints" occurred between 1983 and Gold therapy in rheumatoid arthritis Over 60 years ago Forrestier introduced gold for the management of rheumatoid arthritis (RA).1 His premise was that the disease was related to tuberculosis and that gold salts had an antitubercular effect. Thereafter, confidence in this heavy metal waxed and waned, finally becoming established when the Empire Rheumatism Council concluded from a multicentre controlled trial2,3that intramuscular gold was efficacious in RA. In 1974, Sigler et al4 reported that gold decreased the rate of disease progression as assessed with radiographs, and further controlled studies substantiated the clinical role of the intramuscular preparation by comparison with placebo, oral gold (’Auranofm’), and sulphasalazine.5,6 Nevertheless, there are serious drawbacks to such therapy-lack of efficacy in some patients, toxicity in many, and generally low continuation rates. Some researchers7,8have questioned whether gold really modifies disease at all. In addition, frequent
laboratory tests are required, injections are unpleasant, and there are many alternatives, ranging from the oral gold preparation to the increasingly popular methotrexate and sulphasalazine. In 1977 it was suggested that gold therapy had no role in modem medicine;9 and, with the advent of penicillamine and later methotrexate, this view evoked some sympathy. The picture is as unclear now as it was then. New molecules roll off the production lines almost monthly, but the optimism of clinicians is tinged with increasing cynicism. Should one give monoclonal antibodies directed against CD4, CD5, CD7, or other epitopes or would it be preferable to inhibit angiogenesis or metalloproteins? Maybe antiDR4, macrophage antibodies, soluble T-cell receptors, or T-cell vaccinations would be best. Possibly several drugs should be given in combination; if so, should one choose A--+A + B--+A + B + C, or A+B+C->A+B-->A? It is difficult to decide whether any of these exciting new developments will be good or bad for arthritis or good or bad for the patient. Many doctors fear the
1988. These researchers also noted that the outcome in patients who had received the gold for at least two consecutive years and in those who had not received such therapy was not statistically different. Epstein had previously suggested that there was no place for gold in modem rheumatology.Should one accept these data as being more relevant than those of double-blind controlled trials? Population-based studies have several shortcomings. First, they take no note of the subset of individuals who have done especially well (or badly). Second, without a placebo arm one has to accept that, had no treatment been given, the gold cohort might have fared less well than the non-gold cohort. Third, those not receiving gold may well have received other adequate therapies. These and other confounding variables make it difficult to draw a conclusion from such a study. One can be confident that rheumatologists who favour the use of gold, because of the dramatic improvement in a few patients, will continue to use it, whereas those who have little enthusiasm for the drug will be comforted by this latest report. There is little chance that clinicians’ behaviour will change. Corkill et all1 lately reported the advantages of induction therapy with depot methylprednisolone in conjunction with chrysotherapy-an approach that may enhance efficacy while decreasing toxicity. Such work rekindles interest in both gold and steroids. Lehtinen and Isomakil2 in Finland, in a study of 573 patients, found that gold treatment seemed to prevent premature death in RA, although their hypothesis had been the reverse. Irrespective of the results from many conflicting studies of diverse design, the fact remains that no more than 20% of patients who embark on parenteral gold therapy will still be receiving the drug after a five-year follow-up period, so any positive attributes of gold must be short lived. 1. Fifty years of gold in rheumatoid arthritis. Br Med J 1979; i: 289-90. 2. Research Sub-Committee of the Empire Rheumatism Council. Gold therapy in rheumatoid arthritis: report of a multi-centre controlled trial. Ann Rheum Dis 1960; 19: 95-119. 3. Research Sub-Committee of the Empire Rheumatism Council. Gold therapy in rheumatoid arthritis. Ann Rheum Dis 1961; 20: 315-40. 4. Sigler JW, Bluhm GM, Duncan H, Sharp JT, Ensign DC, McCrum WR. Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 1974; 80: 21-26.
20
syndrome and Miesher’s cheilitis granulomatosa. Melkersson-Rosenthal syndrome is primarily a triad of fissured tongue, facial or labial swelling, and facial palsy but there may be other lesions." Some patients with this syndrome have allergic symptoms,13 slightly raised serum immunoglobulin concentrations, and a raised erythrocyte sedimentation rate.13 The suggestion14
Crohn’s disease). Nevertheless, only very few patients with Melkersson-Rosenthal syndrome have manifested sarcoidosis or Crohn’s disease. 18 Miescher’s granulomatous cheilitis is characterised by isolated labial swelling, and is probably an oligosymptomatic form of Melkersson-Rosenthal syndrome.13 A very few patients have had or have progressed to Crohn’s disease, but again most do not. Thus it is clear that orofacial lesions with noncaseating granulomas on biopsy specimens may arise in the absence of any evidence of intestinal Crohn’s disease. The aetiology of these conditions is unclear, but some appear to be idiosyncratic responses to defmed food constituents or additives or to other exogenous factors. Management should include biopsy of the lesion and exclusion of intestinal Crohn’s disease by haematological and biochemical investigations; if there are abdominal symptoms, bowel radiography and possibly biopsy are indicated. Histological features of oral biopsy specimens in Crohn’s disease and in orofacial granulomatosis are essentially identical. There is oedema of the superficial corium with lymphangiectasia, and both diffuse and focal aggregates of small lymphocytes. In longstanding lesions there may be irregular fibrosis. Non-caseating epithelioid granulomas with or without multinucleated giant cells may be present but are often poorly formed and patchily distributed. Aggregates of mononuclear cells or frank granulomas can sometimes be seen bulging into or blocking lymphatic vessels. Occasionally there is ulceration of the overlying epithelium. Sarcoid granulomas are typically well-formed and discrete or confluent and are usually readily distinguishable from those of orofacial granulomatosis. For gingival lesions the distinction is much harder because of the dense inflammatory overlay. It may therefore be necessary to exclude sarcoidosis by chest radiography, serum angiotensin-converting enzyme measurements, and possibly a Kveim test. The outlook for patients with orofacial granulomatosis is variable and treatment is often unrewarding. Occasionally the condition remits spontaneously, especially in younger individuals.6,19 Some patients have only mild features and require no treatment, although tooth-associated infections should be eliminated.B Facial swelling, oral ulceration, or other lesions will necessitate therapy; a few of these abnormalities resolve with elimination diets but others may require topical, systemic, or intralesional corticosteroids.6,8,13 Danazol may be helpfupo and clofazimine has been effective, at least in Miescher’s granulomatous cheilitis.21 Hydroxychloroquine benefited one patient with Miescher’s cheilitis.22 Salazosulphapyridine, co-
that the condition is a variant of sarcoidosis has not been confirmed,ls although occasional patients have a positive Kveim reaction16 or raised serum angiotensin-converting enzyme concentrations17 (the Kveim reaction is occasionally positive in classic
trimoxazole, metronidazole, azathioprine, or cyclosporin have had little beneficial effect in the few patients in whom they have been tried.6,8,13 Surgical reduction of the facial swelling is probably not warranted or reliably effective.13
5. Ward JR, Williams HJ, Egger MJ, et al. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1983; 26: 1303-15. 6. Williams HJ, Ward JR, Dahl SL, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum 1988; 31: 703-13. 7. Kushner I. Does aggressive therapy of rheumatoid arthritis affect outcome? J Rheumatol 1989; 16: 104. 8. Epstein WV. Parenteral gold therapy for rheumatoid arthritis: a treatment whose time has gone. J Rheumatol 1989; 16: 1291-94. 9. Editorial. Gold therapy in 1975. Br Med J 1975; ii: 156-57. 10. Epstein WV, Henke CJ, Yelin EH, Katz PP. Effect of parenterally administered gold therapy on the course of adult rheumatoid arthritis. Ann Intern Med 1991; 114: 437-44. 11. Corkill MM, Kirkham BW, Chikanza IC, Gibson T, Panayi GS. Intramuscular depot methylprednisolone induction of chrysotherapy in rheumatoid arthritis: a 24-week randomized controlled trial. Br J Rheumatol 1990; 29: 274-79. 12. Lehtinen K, Isomaki H. Intramuscular gold therapy is associated with long survival in patients with rheumatoid arthritis. J Rheumatol 1991; 18: 524-29.
Orofacial
granulomatosis
Oral lesions are common in patients with proven Crohn’s disease of the intestine and include aphthae,l,2 diffuse swellings of the cheeks or lips,2 chronic inflammatory hyperplasia with fissuring and a cobblestone appearance of the mucosa,3mucosal tags,22 vertical fissures in the lips,4 and hyperplastic gingivitis.S These lesions may antedate bowel symptoms, often by several years,and may be the only obvious site of disease.Some patients with oral lesions-between 10% and 48% in various serieshave symptomless intestinal disease.8 Wiesenfeld et al8 have introduced the term orofacial granulomatosis for lesions that resemble those of Crohn’s disease clinically and histologically in patients who do
have accompanying gastrointestinal abnormalities, on the grounds that non-caseating granulomas are often seen in biopsy specimens. A familial pattern has been recognised in some cases of orofacial granulomatosis9 but not all.8 Between 12% and 60% of patients are atopic, and a few patients seem to have specific intolerances to foods or not
additives-eg, cinnamaldehyde, carvone, peperitone, cocoa, carmosine, sun yellow, or monosodium glutamate"—or to materials such as cobalt. 12 The distinction between orofacial granulomatosis with other conditions and non-caseating granulomas--eg, oral Crohn’s disease-may not be easy. Orofacial granulomatosis may be part of a spectrum of disorders that includes MelkerssonRosenthal
