Martti Nissilä

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial

BACKGROUNDnThe treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis.nnnMETHODSn199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat.nnnFINDINGSn87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events were similar in both treatment groups.nnnINTERPRETATIONnCombination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.

Prognosis of Inflammatory Joint Diseases: A Three-year Follow-up Study

The prognosis 3 years after the onset of the disease was studied in 107 patients with definite rheumatoid arthritis, 161 with probable RA or non-specific arthritis, 84 with either ankylosing spondylitis, Reiters disease or reactive arthritis, 14 with psoriatic arthritis and 10 with a systemic connective tissue disease. Prognosis was measured by clinical involvement of joints, radiological erosions in joints, deterioration in joint function, ESR, and working ability. A total of 44% of all patients were symptomless after 3 years. The prognosis was best in patients with an HLA B 27-associated disease and non-specific arthritis, and worst in RA. Two patients died during the follow-up of systemic connective tissue disease and one committed suicide with an overdose of hydroxychloroquine. Two HLA B27-positive patients developed systemic amyloidosis.

Combination drug therapy retards the development of rheumatoid atlantoaxial subluxations

OBJECTIVEnTo compare the efficacy of combination therapy with disease-modifying antirheumatic drugs (DMARDs) versus single therapy with DMARDs in the prevention of early cervical spine changes in patients with rheumatoid arthritis (RA).nnnMETHODSnOne hundred ninety-five patients with recent-onset RA (mean disease duration 8 months) were randomly assigned to receive a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or a single DMARD with or without prednisolone. After 2 years of followup, cervical spine radiographs were taken of 176 of these patients (85 in the combination-therapy group and 91 in the single-therapy group). These radiographs were evaluated, and the findings were correlated with the therapy strategies as well as with peripheral joint destruction and clinical and laboratory variables describing the disease activity.nnnRESULTSnAnterior atlantoaxial subluxation (aAAS), atlantoaxial impaction (AAI; i.e., vertical subluxation), and subaxial subluxation (SAS) were found in only 6 (3.4%), 2 (1.1%), and 5 (2.8%) of the patients, respectively. Interestingly, none of the patients in the combination-therapy group had aAAS or AAI. The incidences of aAAS and AAI in the single-therapy group were 6.6% and 2.2%, respectively. SAS was present in 2 patients (2.2%) in the single-therapy group and in 3 patients (3.5%) in the combination-therapy group. The difference in the incidence of aAAS between the treatment groups was statistically significant (P = 0.029). None of the patients with cervical spine changes achieved remission of RA during the study.nnnCONCLUSIONnIn the present study, the incidence of cervical spine subluxations in patients treated with single-drug therapy was in accord with findings of previous studies. However, none of the patients in the combination-therapy group had aAAS or AAI. These findings suggest that early, aggressive combination-DMARD therapy with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone can prevent or retard the development of rheumatoid atlantoaxial disorders.

Effects of Non-steroidal Anti-inflammatory Drugs and Prednisolone on Synovial Fluid White Cells, Prostaglandin E2, Leukotriene B4 and Cyclic AMP in Patients with Rheumatoid Arthritis

Altogether 53 patients (31 women, 22 men) with definite rheumatoid arthritis were randomly divided into groups of 5-6 patients and treated for one day only with one of the following non-steroidal anti-inflammatory drugs (NSAIDs): acetylsalicylic acid, carprofen, diclofenac, indomethacin, naproxen, proquazone, timegadine, tolfenamic acid or paracetamol, and with prednisolone, in recommended doses. Synovial fluid samples were collected before and after the treatment. White cell count and its differentiation as well as the concentrations of protein, cyclic adenosine-3,5-monophosphate (cAMP), prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were measured from the synovial fluid. Synovial fluid leukocyte counts correlated with PGE2 concentrations, but showed no correlation with LTB4 levels before treatment. Significant changes were seen in the form of lowered PGE2 values following treatment with the clinically and experimentally most potent NSAIDs, and as depressed LTB4 levels following prednisolone treatment. The other markers of inflammation are obviously more resistant, changing only slowly during prolonged treatment, and may thus be, at least in part, secondary to the changes in prostanoids.

Osmic Acid in Rheumatoid Synovitis: A Controlled Study

Ninety-nine adult RA patients with knee joint synovitis were randomized into two groups. The knee joints of the first group (52 patients) were treated with osmic acid and those of the second group (47 patients) with a placebo. After 6 months, the incidence of hydrops and pain was statistically less significant in joints treated with osmic acid. the result was better in joints without advanced radiological destruction. It is concluded that osmic acid is still of benefit in the local treatment of rheumatoid knee joint synovitis at an early stage.

Differences in the Production of Arachidonic Acid Metabolites between Healthy and Rheumatic Synovial Fibroblasts In Vitro: A Preliminary Study

Production of various arachidonic acid metabolites from both endogenous and exogenous substrate was measured using cultures of synovial fibroblasts from healthy and rheumatic synovia. At first, the rheumatic cells showed retarded growth and an altered histological picture. Rheumatic cells produced more 6-keto-PGF1 alpha, the main metabolite of prostacyclin, and prostaglandin E2 than did normal cells, which synthesized more thromboxane B2. Later on these differences diminished or disappeared, except regarding 6-keto-PGF1 alpha. When fairly high concentrations of exogenous arachidonic acid were used, for 2-hour incubation of the cells, the production of identified metabolites, 6-keto-PGF1 alpha, PGF2 alpha, PGE2, PGD2, PGA + PGB and thromboxane B2, was slightly less in rheumatic cells. In general, the main metabolite formed was 6-keto-PGF1 alpha. Some kind of feedback mechanism between prostaglandins and cyclic nucleotides is suggested.

D-penicillamine effects on prostanoid production in adherent rheumatic synovial cells in primary culture.

The effect of D-penicillamine (DPA) on immunoreactive prostanoid concentrations was studied in a primary culture of adherent synovial cells from patients suffering from rheumatoid arthritis (RA). DPA in clinically achievable concentrations increased the levels of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) and reduced those of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) synthetized from endogenous substrate. The capacity for PGE2 and 6-keto-PGF1 alpha production in the presence of exogenous arachidonic acid was decreased by DPA. These effects may be connected with the antirheumatic and immunosuppressive action of DPA.

HLA-D Antigens in Rheumatoid Arthritis and Toxicity to Gold and Penicillamine

The frequencies of HLA-D antigens were investigated in 77 Finnish patients who met the ARA criteria of classical or definite rheumatoid arthritis. The control material consisted of healthy blood donors. HLA-Dw4 was significantly (p less than 0.01) increased and HLA-Dw2 significantly (p less than 0.01) decreased in the patients. All HLA-Dw4-positive patients belonged to the seropositive group and in comparison with controls HLA-Dw4 antigen was increased highly significantly (p less than 0.001) in the seropositive patients. With respect to HLA-Dw4 antigen, the seropositive and the seronegative group differed significantly (p less than 0.05). All patients had received penicillamine treatment and 75 of them gold treatment before penicillamine. No significant associations were noted between any HLA-D antigen and gold or penicillamine toxicity. The previous gold toxicity seemed to be a significant factor with respect to the subsequent penicillamine toxicity.

HLA-B27 AND CLINICAL CHARACTERISTICS OF REACTIVE ARTHRITIS

B27- (6%) patients (p<0.05). During acute RD, mucocutaneous symptoms were the only manifestation more frequent in B27+ (50%) thaninB27- (17%)RDpatients(p<0.01). At the follow-up study mean 6 years later, peripheral joint symptoms occurred in two thirds of the RD patients with or without HLA-B27. Back pain was slightly more common in B27+ patients (44% vs. 22%; NS).