ORAL STEROIDS AS BRIDGE THERAPY IN RHEUMATOID ARTHRITIS PATIENTS STARTING WITH PARENTERAL GOLD. A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL

The efficacy of oral prednisone as bridge therapy in rheumatoidarthritis (RA) was studied. Forty patients starting aurothioglucosewere randomized to receive either prednisone or placebo for18 weeks. The dose was 10 mg/day in the first 12 weeks, 7.5mg/day in weeks 13 and 14, 5 mg/day in weeks 15 and 16, and2.5 mg/day in weeks 17 and 18. Patients were followed for 44weeks. We found that disease activity was significantly lowerin the prednisone group as early as week 1 and continued upto week 12. Response to prednisone was noticed in 60% of thepatients. After tapering prednisone, a rebound deteriorationwas noticed at weeks 20 and 24 in 58% of the responders. Nosignificant differences in X-ray progression were found betweenthe two groups. We concluded that oral prednisone (10 mg/day)significantlyreduces short-term disease activity in 60% of patients withactive RA. The rebound deterioration after tapering the dosemeans that bridge therapy with prednisone using this dose-reductionscheme is not recommended. KEY WORDS: Rheumatoid arthritis, Prednisone, Efficacy     

A RANDOMIZED TRIAL OF TESTOSTERONE THERAPY IN MALES WITH RHEUMATOID ARTHRITIS

Thirty-five male patients, aged 34–79 yr, with definiterheumatoid arthritis (RA) were recruited from out-patient clinicsand randomized to receive monthly injections of testosteroneenanthate 250 mg or placebo as an adjunct therapy for 9 months.Endpoints included disease activity parameters and bone mineraldensity (BMD). At baseline, there were negative correlationsbetween the ESR and serum testosterone (r = - 0.42, P < 0.01)and BMD (hip, r = – 0.65, P < 0.01). A total of 29.6%of all patients had at least one vertebral fracture, most havingmultiple fractures. Back pain, however, was not more prevalentin fracture patients (55% vs 50%). Disease activity was significantlyhigher in the fracture group (joint score P < 0.05, rheumatoidfactor P < 0.01). Thirty patients completed the trial, 15receiving testosterone and 15 receiving placebo. There weresignificant rises in serum testosterone, dihydrotestosteroneand oestradiol in the treatment group. There was no significanteffect of treatment on disease activity overall, five patientsreceiving testosterone underwent a ‘flare’. Differencesin mean BMD following testosterone or placebo were non-significant(spine: +1.2% vs –1.1%; femur –0.3% vs +0.3%). Therewas no suggestion of a positive effect of testosterone on diseaseactivity in men with RA. KEY WORDS: Rheumatoid arthritis, Male, Disease activity, Bone density, Vertebral fracture, Testosterone     

METHOTREXATE AND SULPHASALAZINE AS COMBINATION THERAPY IN RHEUMATOID ARTHRITIS

Sulphasalazine (SASP) and methotrexate (MTX) are well-establishedtreatments for RA but the use of these drugs in combinationhas been avoided as both have antifolate activity. In this paperwe report our experience with 32 patients treated with the combinationMTX/SASP and compare the toxicity and tolerability of the combinationwith 63 patients treated with MTX alone. The median durationof exposure to the combination was 23 months. Nineteen patientshave continued this regime for over 18 months. Five patientson MTX/SASP combination discontinued MTX, in four cases dueto toxicity and in one because MTX/SASP was ineffective. In17 patients on MTX alone, the drug was withdrawn permanently.In seven cases the cause was toxicity including two patientswith severe reactions. In patients known to tolerate SASP alone,the combination of MTX/SASP is also well tolerated. In our experienceof 48 patient-years of such combination therapy, there is noincrease in toxicity compared to therapy with MTX alone in RA. KEY WORDS: Methotrexate, Sulphasalazine, Combination therapy, Toxicity, Rheumatoid arthritis     

SULPHASALAZINE IN PSORIATIC ARTHRITIS: A RANDOMIZED, MULTICENTRE, PLACEBO-CONTROLLED STUDY

A prospective double-blind, placebo-controlled, randomized studyof 24 weeks duration was carried out comparing the efficacyand tolerability of sulphasalazine (SSZ) versus placebo in patientswith psoriatic arthritis. A total of 120 patients were includedin nine centres. All patients had active disease and fulfilledthe criteria of definite psoriatic arthritis of at least 3 monthsduration. They received either SSZ (2.0 g/day) or placebo. Efficacyvariables included pain, patient's overall assessment of jointand skin improvement, morning stiffness, Ritchie articular index,ESR and CRP. An intention-to-treat (TTT) analysis was performedfor the 117 patients who qualified (three patients did not qualifydue to missing data after baseline). A per-protocol analysiswas performed for the 81 patients who completed the 6 monthsstudy period (SSZ = 38, placebo = 43). Major reasons for withdrawalwere inadequate response (SSZ = 4, placebo = 7) and adverseevents (SSZ = 8, placebo = 12). Pain was the only statisticallysignificantly different primary outcome variable at end pointin favour of SSZ in the ill analysis. No significant differenceswere present in other clinical or biological variables, althoughthere was a trend in favour of SSZ for some variables. SSZ,at a dose of 2.0 g/day, appeared to be a safe treatment in patientswith psoriatic arthritis. At this dosage, its efficacy was onlydemonstrated for the pain variable. KEY WORDS: Psoriatic arthritis, Treatment, Sulphasalazine     

APLASTIC ANEMIA IN ASSOCIATION WITH GOLD THERAPY FOR RHEUMATOID ARTHRITIS

Abstract: Over a ten year period five patients developed aplastic anemia in association with gold therapy for rheumatoid arthritis. None of these patients was suitable for bone marrow transplantation due to the lack of a compatible sibling. Four patients with severe aplastic anemia died, despite intensive haemopoietic support and trials of gold chelating agents. Survival ranged from 22 to 103 days (mean 55 days) with death in each case being due to a combination of bleeding and infection. The remaining patient with moderate aplasia survived, recovering over a period of two to three years.     

BIOAVAILABILITY OF HYDROXYCHLOROQUINE TABLETS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Nine patients with RA received two doses of 155 mg racemic hydroxychloroquineeach, as a tablet and by i.v. infusion, in a randomized cross-overdesign study. Blood concentrations over the first 32 h followingeach dose were determined. Bioavailability was estimated usinga sequential exponential least squares deconvolution method. The mean fraction absorbed from the tablet was 0.79 (range 0.39to 1.27). The mean absorption lag-time was 1.3 h (range 0.5to 3.7 h) and the mean time for 50% absorption was 4.3 h (range1.9 to 10.3 h). Mean rate and extent of hydroxychloroquine absorptionwere not significantly different from that previously reportedfor healthy volunteers, although the interindividual variabilityin absorption parameters was greater in the patient group. Variabilityin the extent of absorption would lead to differences in steady-statehydroxychloroquine concentrations between patients, potentiallycontributing to the variability in response observed in clinicalpractice. KEY WORDS: Pharmacokinetics, Hydroxychloroquine, Bioavailability Present address: Department of Pharmacy, University of Manchester,Manchester M13 9L     

THE CYCLING OF COMBINATION ANTIRHEUMATIC DRUG THERAPY IN RHEUMATOID ARTHRITIS

In this open pilot study a combination of hydroxychioroquine,prednisolone and alternating months of treatment with sulphasalazineor oral weekly pulse methotrexate has been investigated in 16patients with rheumatoid arthritis (RA) refractory to a totalof 67 disease suppressive medications. Results at 3 months indicatedsignificant improvements in visual analogue score for pain,joint count, Ritchie index, scale of disability related to activitiesof daily living, ESR, rheumatoid factor and C-reactive protein.This degree of improvement, however, was not maintained 6 and12 months after commencement of treatment. Pain score, Ritchieindex and ESR were the only parameters demonstrating significantimprovement at 12 months. Therapy was terminated in eight patients,half due to lack of efficacy and half because of side effects. KEY WORDS: Arthritis, Treatment, Methotrexate, Sulphasalazine, Antimalarials, Corticosteroids     

LEUCOPENIA IN RHEUMATOID ARTHRITIS: RELATIONSHIP TO GOLD OR SULPHASALAZINE THERAPY

Leucopenia is one of the most worrying of the many toxic effectsof second-line drug therapy for rheumatoid arthritis, and muchtime and energy is expended in screening for it. Sulphasalazine(SASP) is generally claimed to be safer than some alternativesecond-line drugs but the reported incidence of leucopenia hasvaried widely. We have examined, retrospectively, all recordsof blood counts before, during and after treatment in 326 SASPtreated patients and in 213 on gold. Leucopenia on at leastone occasion occurred in up to 10% of patients on both drugsbut usually recovered spontaneously in spite of continued therapy.‘Serious’ leucopenia leading directly to drug withdrawalwas a rare event occurring in only one SASP patient and in twopatients receiving gold treatment. Most episodes of leucopenia do not require drug withdrawal andmay not be drug related. KEY WORDS: Leucopenia, Neutropenia, Sulphasalazine, Gold, Rheumatoid arthritis.     

PROSPECTIVE LONG TERM FOLLOW-UP OF METHOTREXATE THERAPY IN RHEUMATOID ARTHRITIS: TOXICITY, EFFICACY AND RADIOLOGICAL PROGRESSION

We followed all 128 patients started on methotrexate (MTX) forrheumatoid arthritis (RA) over a 4-year period. Forty-nine werefollowed for over 3 years. Forty-three patients discontinuedtreatment, 23 because of toxicity, 15 for inefficacy and fivefor other reasons. Forty-seven of the 75 followed on treatmentfor over 2 years had hand radiographs available before and afterthis treatment period. None showed improvement and 15 showedmarked deterioration. Patients' acceptance of this therapy wasgood although most were noted objectively to have persistentdisease activity. We would recommend that if MTX is to be used,a more aggressive approach be adopted to reduce not only thesymptoms but the signs of active disease. KEY WORDS: Disease-modifying antirheumatic drugs, Side effects, Radiographs, Haematology, Liver, Kidney     

GOLD AND PULMONARY FUNCTION IN RHEUMATOID ARTHRITIS

The effect of gold therapy on pulmonary function in rheumatoidarthritis has been studied prospectively in a group of 14 patientsand retrospectively in 96 patients. There was no evidence thatgold had any adverse effect on pulmonary function. KEY WORDS: Rheumatoid Arthritis, Gold, Pulmonary function     

BREAST FEEDING, OTHER REPRODUCTIVE FACTORS AND RHEUMATOID ARTHRITIS. A PROSPECTIVE STUDY

The evidence regarding reproductive events as risk factors forrheumatoid arthritis (RA) is not conclusive. In the presentstudy a population-based cohort consisting of 63 090 women werefollowed from 1961 to 1989. Detailed data on reproductive factorswere collected through personal interviews in the period 1956–9.The endpoint used was mention of RA on the death certificate.Mortality rate ratios were estimated by Poisson regression,controlling for various demographic variables. During 1 485400 person-yr of observation, a total of 355 cases with RA mentionedon the death certificate were identified. Total time of lactationwas associated with a decreased mortality of RA, with an approximatedose–response relationship. The results did not supporta role of parity, age at first and last birth, or age at menarche’andmenopause in the development of RA. This protective effect oflactation on the development of RA has not previously been described,and since a definite biological explanation is lacking, theassociation should be confinned in other populations. KEY WORDS: Rheumatoid arthritis, Reproductive factors, Lactation, Mortality     

SULPHASALAZINE ALONE OR IN COMBINATION WITH D-PENICILLAMINE IN RHEUMATOID ARTHRITIS

Thirty patients (22 women) with active rheumatoid arthritisparticipated in an open study of 6 months' treatment with eitherenteric-coated sulphasalazine (SASP) or SASP plus D-penicillamine(DPA). Patients were assessed at regular intervals using a numberof clinical and biochemical tests designed to detect specificantirheumatic activity. There were significant improvements in clinical and laboratoryvariables with both regimens consistent with second-line activity.Improvements were greater and more numerous with combinationtherapy. At the end of the trial period, there were nine ‘responders’in the SASP/DPA group but only six in the SASP group. Neitherefficacy nor toxicity could be related to patient acetylatorstatus. Nausea and dyspepsia were frequent problems with both treatmentregimens but dysgeusia and thrombocytopenia were confined tothe SASP/DPA group. Study withdrawals were twice as common withcombination therapy. These results suggest that a combination of SASP and DPA ismore potent than SASP alone but at the expense of poorer patienttolerance. KEY WORDS: Rheumatoid arthritis, Sulphasalazine, D-Penicillamine, Combination therapy     

THE PATTERN OF RHEUMATOID ARTHRITIS IN THE INDIAN POPULATION: A PROSPECTIVE STUDY

Evaluation of polyarthritis in 110 patients in civilian andarmed force life revealed 89 with rheumatoid arthritis (RA).In the Indian population, RA seems milder and confined to thejoints. A substantial number of male patients appeared to sharefeatures with spondarthritis, often in HLA-B27 positive individuals. KEY WORDS: Prognosis, Polyarthritis, Rheumatoid factor, Tissue type, Spondarthritis.     

HEPATITIS AND NEUTROPENIA SECONDARY TO GOLD THIOMALATE THERAPY FOR RHEUMATOID ARTHRITIS

Abstract A 37 year old female with rheumatoid arthritis developed clinical and biochemical evidence of hepatitis after receiving 80 mg of sodium aurothiomalate. Inadvertent rechallenge with sodium aurothiomalate led to recurrence of the biochemical abnormalities and a profound neutropenia and eosinophilia.     

SULPHASALAZINE THERAPY IN RHEUMATOID ARTHRITIS: QUALITATIVE CHANGES IN LYMPHOCYTES AND CORRELATION WITH CLINICAL RESPONSE

Clinical and immunological parameters in 14 patients with rheumatoidarthritis (RA) receiving sulphasalazine (SASP) were evaluated,to determine whether their clinical response was reflected byany quantitative changes in their peripheral blood lymphocytesafter 12 weeks. Whilst disease activity markers fell significantly,no such changes were noted in the percentage or absolute numbersof lymphocytes or their subsets. The lymphocytes of a further 21 patients before and after receivingSASP for 12 weeks were then studied qualitatively. The suppressionmediated by in vitro SASP on ex vivo PHA stimulated lymphocytesshowed a decrease at 12 weeks. This change was more marked andreached statistical significance only in those patients whoshowed a good clinical response. It is postulated that thismay in some way be related to expression of activation markersand concomitant SASP binding. KEY WORDS: Lymphocyte transformation, Mitogen, Rheumatoid arthritis, Sulphasalazine     

SULPHASALAZINE IN RHEUMATOID ARTHRITIS: HAEMATOLOGICAL PROBLEMS AND CHANGES IN HAEMATOLOGICAL INDICES ASSOCIATED WITH THERAPY

This prospective study documents the haematological responsesin 300 rheumatoid patients (RA) treated with sulphasalazine(SASP) for between 1 and 9 years. It also examines the effectof SASP on the total white cell and platelet counts over 2 yearsin relation to disease activity in 80 RA patients. Neutropenia occurred in six (2%) (three severe–neutrophilcount >0.8xl09/l) after 3 and 12 weeks. The drug was withdrawnin six immediately and in one patient after 21 months when theneutrophil count fell to 0.7x 10⁹⁹/1. An additional 11 (3.7%)developed mild or transient leucopenia between 2 weeks and 24months, and eight continued therapy. Thrombocytopenia occurredin one patient at 18 weeks associated with other reactions.Four with Felty's syndrome developed a further fall in the totalWBC associated with thrombocytopenia in two. A rise in meancell volume was common (72%), and macrocytosis (MCV>98 fl)occurred in 27 (9%). Macrocytic anaemia was rare (>1%). Allhaematological problems were reversible. In 80 patients treated with SASP for 2 years there was a significantfall in the median white cell and platelet counts at 3 monthsassociated with improvement in disease activity. KEY WORDS: Rheumatoid arthritis, Neutropenia, Leucopenia, Thrombocytopenia, Anaemia, Macrocytosis, Folic acid, Sulphazalazine, Monitoring     

DENTAL STUDY IN PATIENTS WITH RHEUMATOID ARTHRITIS

Twenty-one patients with rheumatoid arthritis took part in acomparison of three toothbrushes, each used for one month ina randomized trial. The three toothbrushes were a conventionaltoothbrush with modified handle to allow ease of gripping, anelectric toothbrush, and thirdly a fingerstall attached to anormal toothbrush. There was no change in the patients' rheumatoid status duringthe trial. The patients were scored for plaque and gingivalchanges but no difference was found between the three toothbrushes. We recommend a standard toothbrush with a modified grip forthe rheumatoid hand; the extra expense of an electric toothbrushcannot be justified. ^*Paper read at the Annual Meeting of the British Associationfor Rheumatology and Rehabilitation, London, 17 April, 1980.     

NIGHT MEDICATION IN RHEUMATOID ARTHRITIS: II. COMBINED THERAPY WITH INDOMETHACIN AND DIAZEPAM

Seventeen of eighteen patients hospitalized for active rheumatoidarthritis completed a three-day, randomized, double-blind comparisonof 100 mg indomethacin, 100 mg indomethacin with 10 mg diazepamand matching placebo as night medication. The results showeda consistent pattern in the four functions measured—pain,morning stiffness, sleep score and patient preference. In each,indomethacin proved superior to placebo and the combined therapybetter than indomethacin alone. From this it has been concludedthat the combination of indomethacin and diazepam should nowbe considered the treatment of choice for maximum control ofnight pain and morning stiffness in rheumatoid arthritis.     

A 6-MONTH RANDOMIZED DOSE RANGE STUDY OF OM-8980 IN RHEUMATOID ARTHRITIS

Sixty patients with active RA were evaluated over 6 months ina double-blind randomized dose range multicentre study comparingthe efficacy and tolerance of three different doses of the slow-actinganti-rheumatic bacterial extract OM-8980 (6, 24 and 48 mg ofactive principle). No patients were withdrawn during the study.At the end of the 6-month trial, signifi cant improvements wereobserved for the different RA signs and symptoms (Ritchie index,morning stiffness, swollen joints, grip strength, ESR, painscale and categories) as well as for the concomitant intakeof symptomatic drugs in the 24-mg dose group with respect tothe 6-mg group and without significant differences between the24- and 48-mg groups. Tolerance was very good with nine minorand transient side effects (five itching and four diarrhoea)reported altogether by seven patients, without establishmentof a dose-effect correlation. In conclusion, the two higher doses of OM-8980, 24 and 48 mg,were significantly more efficient than 6 mg, with the effectof the 24-mg dose being even slightly superior to the 48-mgdose, confirming the former as the optimal and well tolerateddose for the treatment of RA. KEY WORDS: Slow-acting anti-rheumatic drugs, Immunomodulation, Efficacy, Safety, Double-blind trial