Markku Hakala

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.

Anxiety and depression in a community-based rheumatoid arthritis population

OBJECTIVEnTo assess anxiety and depression and their explanatory factors in rheumatoid arthritis (RA) in a community-based population.nnnMETHODSnThe subscales of the Arthritis Impact Measurement Scales (AIMS) for anxiety and depression were used, and the Health Assessment Questionnaire (HAQ) was used for the assessment of disability. Cross-tabulation and multivariate logistic regression analysis were used to evaluate which variables best describe the patients with either high or low depression and anxiety scores.nnnRESULTSnNearly 20% of our patients had probable depression (AIMS depression subscale score > or =4), a figure comparable to earlier hospital-based series. Most of the AIMS anxiety subscale variability was explained by poor physical function and the male sex, while the AIMS depression subscale variability was mostly explained by poor physical function, comorbidities, and social inactivity.nnnCONCLUSIONnIn our cross-sectional, community-based RA series, depression was equal to the figures previously reported from hospital-based series. Poor physical function was a powerful explanatory factor of both depression and anxiety.Objective: To assess anxiety and depression and their explanatory factors in rheumatoid arthritis (RA) in a community-based population. Methods: The subscales of the Arthritis Impact Measurement Scales (AIMS) for anxiety and depression were used, and the Health Assessment Questionnaire (HAQ) was used for the assessment of disability. Cross-tabulation and multivariate logistic regression analysis were used to evaluate which variables best describe the patients with either high or low depression and anxiety scores. Results

Prevalence of cervical spine subluxations and dislocations in a community-based rheumatoid arthritis population

The prevalence of rheumatoid cervical spine subluxations was studied by plain radiography in a population of 13,000 adults with 98 out of 103 detected cases of rheumatoid arthritis. Anterior atlantoaxial subluxation (AAS) of 4 mm or more was found in 33% of the cases and vertical dislocation in 14% or 27% depending on the diagnostic method. Lateral, posterior and subaxial subluxations were found in 14%, 2% and 21% respectively. These figures agree with former findings in clinical populations. One patient had been operated on for subaxial subluxation. Anterior AAS of 9 mm or more was found in four cases, subaxial subluxation of more than 4 mm in one case and a combination of anterior AAS of 6-9 mm and vertical dislocation in six cases. If these limits are taken as indications for surgery, as recommended earlier, about 10% of the RA patients should be operated, an unrealistic figure. It is concluded that intolerable pain or cervical myelopathy, and not the plain radiological findings alone, are indications for surgery. Most cases are treated by conservative methods.

Magnetic resonance imaging and magnetic resonance sialography of parotid glands in primary Sjogren's syndrome.

OBJECTIVEnTo look for structural parotid gland changes on magnetic resonance (MR) imaging and MR sialography of primary Sjögrens syndrome (SS) patients and healthy control subjects and to compare these methods with each other.nnnMETHODSnMR imaging and MR sialography of both parotid glands were performed on 26 patients and 7 healthy controls. Bilateral surface coils were used to obtain high spatial resolution.nnnRESULTSnTwenty-two of the 26 patients had abnormalities on MR imaging. Twenty-one had a nodular or dendritic parenchymal pattern, 5 had cavities, and 6 had duct dilatations. On MR sialography, 25 of the 26 patients had abnormalities of the ducts, and 16 of them also had cavities. One patient and all 7 controls had normal results with both methods. The structural appearance of the parotid glands on MR images had marginal linear association with the duct system changes but no correlation with the cavitary changes seen on MR sialography. Furthermore, duct system abnormalities did not correlate with cavitary changes. Both parenchymal and sialographic abnormalities were associated with the presence of Ro/SSA antibodies but not with age of the patient, disease duration, salivary flow rate, or the presence of hypergammaglobulinemia or extraglandular manifestations.nnnCONCLUSIONnMR imaging and MR sialography are noninvasive methods that provide definitive information of morphologic changes in parotid glands and can be used as diagnostic indicators of primary SS. Because these methods give information on different aspects of glandular pathology, both should be performed when evaluating parotid glands of SS patients. MR sialography is more sensitive, but conventional MR imaging gives complementary information on the progressive pathologic changes of glandular parenchyma.

Primary Sjögren's syndrome with severe central nervous system disease

OBJECTIVEnCentral nervous system (CNS) involvement in primary Sjögrens syndrome (pSS) is controversial with regard to frequency, significance, and etiology.nnnMETHODSnWe describe a young woman with pSS and severe CNS disease and review the literature on the pathophysiology, clinical significance, symptoms, diagnostic examinations, and treatment of CNS disease with concomitant pSS (CNS-SS).nnnRESULTSnOur patient with pSS had a 5-month history of benign lymphadenopathy and myositis, after which she developed severe CNS disease, vasculitic lesions on her hands, and a neurogenic bladder attributable to spinal cord involvement. The diagnosis was based on the clinical picture and the results of a brain magnetic resonance imaging (MRI) scan, electroencephalography (EEG), and cerebrospinal fluid (CSF) analysis. The disease did not respond to corticosteroids, but the administration of cyclophosphamide resulted in recovery. In the literature, the incidence of CNS-SS varies widely, from rare to incidence rates of 20% to 25%. The clinical picture is diverse, ranging from mild cognitive symptoms to fatal cerebrovascular accidents. The pathophysiology of CNS-SS is unclear, specific diagnostic methods are not available, and diagnosis is based on the clinical picture and a combination of examinations. MRI is the most sensitive test and cerebral angiography the most specific. CSF reflects involvement of the leptomeninges, and EEG is nonspecific. There are no controlled studies of the treatment of CNS-SS. Regimens for vasculitis are commonly used.nnnCONCLUSIONSnCNS-SS is uncommonly recognized and difficult to diagnose. Increasingly accurate and available diagnostic examinations will yield more information about the association of CNS disease with pSS.

TH1 Cytokines are Produced in Labial Salivary Glands in Sjögren's Syndrome, but also in Healthy Individuals

The aim of the present study was to assess the T cell cytokines IFN-gamma, IL-2, IL-4 and IL-5 in labial salivary glands (LSG) in Sjögrens syndrome (SS) and healthy controls using RT-PCR and immunohistochemistry. IFN-gamma is always or almost always produced in SS and in healthy controls. IL-2 was also found in some samples, but IL-4 and IL-5 were not. Less than 2% of all inflammatory mononuclear cells contained immuoreactive IFN-gamma or IL-2. Cytokine mRNA profile in LSGs in SS is skewed towards a T(H)1 pattern. The classical T(H)1 cytokines are also produced in normal glands, even in the absence of foci. T(H)1 type response may play an active role as part of the mucosal associated lymphoid tissue/responses, perhaps in prevention of reactivation of latent viruses. This may also make the exocrine glands a locus minoris resistentiae when the self tolerance is broken.

More Evidence of Distinctive Features of Mixed Connective Tissue Disease

A comparison of clinical, immunological and HLA-D region antigen features was made between 22 patients with mixed connective tissue disease (MCTD) and 118 patients with systemic lupus erythematosus (SLE), scleroderma or primary Sjögrens syndrome. The MCTD patients had hypergammaglobulinemia more often than did those with SLE and scleroderma, but had less skin ulceration, serositis, nephritis, central nervous system disease and hypocomplementemia than the SLE patients. The frequencies of HLA-DR4 and its Dw4 subtype were significantly increased in MCTD as compared with both the other patient groups and healthy controls. Anti-RNP antibodies and the clinical characteristics together seem to illustrate a disease syndrome which is clinically and genetically distinct and fits with the prevailing concept of MCTD.

Association of different HLA antigens with various toxic effects of gold salts in rheumatoid arthritis.

An association of gold induced proteinuria with HLA-D(R)3 has been reported. To investigate other possible relationships between gold toxicity and HLA antigens we studied 85 patients with rheumatoid arthritis (RA) divided into four subgroups: patients with gold induced interstitial pneumonitis, mucocutaneous lesions, proteinuria, and patients without gold toxicity. The HLA frequencies in patient groups and 283 healthy controls were compared in different pairwise combinations. Gold induced pneumonitis was associated with HLA-B40 and Dw1. An association between gold induced proteinuria and HLA-Dw3 was also seen. The increased prevalence of Dw4 in RA was observed only in the control patient group without gold induced side effects. The frequencies of HLA-B7 and Dw2 were decreased in all patient groups compared with the control population. These results further support the view of the heterogeneity of RA as manifested by the unique HLA associations with resistance and susceptibility to gold induced side effects characterising different subgroups.

Relationship of rheumatoid factor to lung diffusion capacity in smoking and non-smoking patients with rheumatoid arthritis

We studied the relationship of serum rheumatoid factor (RF) and certain other variables to lung diffusion capacity for carbon monoxide (DLCO) in patients with rheumatoid arthritis (RA). In non-smoking patients none of the examined variables correlated significantly to DLCO whereas in smokers RF showed a significant (p < 0.01) negative correlation in this respect. These results indicate that smoking in connection with RF may contribute to reduced DLCO in RA patients.

HLA Markers in a Community-based Rheumatoid Arthritis Series

We wanted to investigate whether rheumatoid arthritis (RA) patients, defined by the American College of Rheumatology (ACR) 1987 criteria and selected from one community by the help of the official Finnish data registers, share the common HLA susceptibility genes. The HLA frequencies of 88 RA patients representing 85% of the prevalent cases of RA in the community were compared with those of 188 healthy controls. Fifty-four per cent of the index cases with RA had DR4 compared with 30% of the healthy controls (P <0.001). The RA susceptibility sequence was found in 75% of the DRB1 genes in the index cases, but it did not correlate with the severity of the disease. The frequency of DR3 was not increased in RA patients but it was associated with features of severe disease, that is, with a high erythrocyte sedimentation rate (P<0.05), extra-articular disease (P<0.01) and prostheses in large joints (P<0.05). According to our results community-based RA patients satisfying the new ACR criteria show the common DR4 association. DR3 was the only HLA allele which showed some disease-modifying effect correlating with the severity of RA.