VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA).

The human antibody repertoire has been demonstrated to have a marked V-gene-dependent bias that is conserved between individuals. In RA patients, certain heavy chain V genes (VH) have been found to be preferentially used for encoding autoantibodies. To determine if such preferential use of VH genes in autoantibodies is associated with a general distortion of the V gene repertoire in RA patients, the VH composition of peripheral blood B cells was analysed among four RA patients and four age- and sex-matched healthy controls. Usage of individual VH genes (eight VH3 and three VH4 genes tested by hybridization with a set of gene-specific oligonucleotide probes) was highly biased among RA patients, but no evidence of a distortion in the bias was observed compared with healthy controls. However, the occurrence of somatic mutations in these VH genes (estimated by differential hybridization with motif-specific oligonucleotide probes targeted to CDR and FR of the tested genes, and by DNA sequence analysis) was strikingly different between patients and healthy subjects. The number of VH3 rearrangements that had accumulated somatic mutations and the number of mutations per rearrangement were significantly elevated in three of the four RA patients. A slight but not significant elevation in mutations among rearranged VH4 genes was also observed in these patients. These data suggest that although usage of individual VH genes among peripheral blood B cells is not affected by the disease, the autoimmune process may involve a significant fraction of the B cell compartment.

Erosive rheumatoid factor negative and positive rheumatoid arthritis are immunogenetically similar.

OBJECTIVE: The relationship between rheumatoid factor positive (RF+) and rheumatoid factor negative (RF-) rheumatoid arthritis (RA) is controversial. We sought to determine whether the HLA genes conferring susceptibility for erosive RF+RA are also prevalent in patients with erosive RF-RA. METHODS: DNA-based HLA typing for DRB1, DQB1, and DPB1 was performed on 16 consistently RF--patients with erosive RA. RESULTS: Thirteen of 16 (81%) RF-RA patients had the HLA susceptibility genes DRB1 *0401, *0404, or *0101, which are associated with RF+RA, as compared to 46% of normal controls (p = 0.017). By contrast, no associations with HLA-DQB1 and HLA-DPB1 alleles were apparent. CONCLUSION: Specific HLA susceptibility alleles are prevalent in patients with erosive RA, regardless of RF status, suggesting a similar immunogenetic basis for RA in these patients.

Inverting the therapeutic pyramid: observations and recommendations on new directions in rheumatoid arthritis therapy based on the author's experience.

In evaluating current therapy for rheumatoid arthritis (RA), it is increasingly being recognized that sequential single-drug treatment, as exemplified by the traditional therapeutic pyramid, is often too little, too late, and ineffective in preventing disease progression or joint damage in patients with "at-risk," aggressive synovitis or what might be called type 2 RA. Designation of drugs as either antiinflammatory or disease-modifying is not supported by the author's experience. Evidence exists that prevention of joint damage correlates best with control of clinical and laboratory measures of inflammation, regardless of the medication used. The earlier and more effective the control of the inflammation, the better the patient response. Until a major breakthrough occurs, the author recommends that patients with aggressive RA be treated with a combination of fast-acting and slow-acting medications to achieve early control and then "bridge down" to a simplified maintenance program. Retrospective observation by the author of 54 patients with early, intermediate, and late disease treated with combinations of prednisone, methotrexate, auranofin, hydroxychloroquine, and azathioprine showed maximum response in patients with disease duration of less than 2 years, minimal toxicity, and lack of erosions in patients with control of inflammation. Twelve patients with inflammation not initially suppressed by prednisone and methotrexate had improved control with additional drugs in combination, including auranofin, hydroxychloroquine, and azathioprine. After inflammation was controlled, reduction of prednisone and methotrexate doses was possible in 60% of patients, primarily those with early disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Approaches to the management of rheumatoid arthritis: rationale for early combination therapy.

In evaluating current therapy of RA, it is becoming recognized that sequential single drug treatment, as exemplified by the traditional therapeutic pyramid, is often too little and too late in patients with aggressive 'at risk' synovitis. Evidence exists that prevention of joint damage correlates best with control of clinical and laboratory measures of inflammation, regardless of the medication used. Until a major breakthrough occurs in this disease, it is recommended that patients with 'at risk' RA be treated aggressively to achieve early control of inflammation, and then 'bridge down' to a simplified maintenance programme. While currently available fast and slow acting drugs might be used in combination today for early induction therapy, newer drugs, cancer chemotherapeutic preparations, biologic agents, or novel therapies may prove more effective and superior tomorrow. Control trials will be necessary to establish the most effective and least toxic induction and maintenance programmes.

The need for aggressive therapy of rheumatoid arthritis.

We are on the threshold of a new era in the treatment of RA if we learn from the experience of the past and utilize new techniques and therapeutic modalities that the future will bring. New strategies and treatment of RA in the future will need to include earlier recognition of progressive disease, earlier interventions, new preparations for use in therapeutic armamentarium, combinations of agents, and monitoring of long-term outcomes to assess results over 5 to 10 years. There is always concern about new therapies and strategies. As noted by Huskisson, however, "In the absence of knowledge about the cause of disease and the mode of action of the drugs, the only way forward is by clinical trials of different preparations. With trial, there is always the risk of error." Our greatest error, however, will be if we ignore lessons from the past, fail to control the inflammatory process early, and continue to spend years writing "doing well" in the charts of patients who become progressively disabled before our eyes.

Challenging the therapeutic pyramid: a new look at treatment strategies for rheumatoid arthritis.

Traditional therapy of rheumatoid arthritis (RA) has been dominated by the therapeutic pyramid. This approach is not working. The designation of drugs as either antiinflammatory or disease modifying is not borne out by experience. We possess a number of drugs, each only partially effective against inflammation, that work by poorly understood mechanisms. Until a major breakthrough appears, it is proposed to treat RA with a combination of these medications early in the disease course, to gain control of the inflammation, and then bridge to a simplified program by withdrawing drugs sequentially.

Reforming the pyramid. A plan for treating rheumatoid arthritis in the 1990s.

Standard treatment of rheumatoid arthritis as illustrated by the pyramid does not prevent joint damage in most patients. The concept that slow-acting drugs are uniquely disease modifying is not supported by experience. Disease modification correlates best with control of inflammation and this has been demonstrated with prednisone. Many medications working by different mechanisms have a partial or temporary effect on inflammation. Following the example of cancer chemotherapy, we propose the step-down bridge, a therapeutic plan in which a combination of drugs is used to control inflammation early in the disease before joints become damaged. Medications are then sequentially discontinued as inflammation remains controlled.

Remodeling the pyramid--a concept whose time has come.

It is clear that the traditional treatment program, as illustrated by the pyramid, does not suppress inflammation in most patients with RA to an extent sufficient to prevent joint damage. There is no basis for the concept that slow acting drugs are uniquely disease modifying. Disease modification correlates best with control of inflammation. Contrary to popular wisdom, this has been best demonstrated with prednisone. The arbitrary concept of a drug being either antiinflammatory or disease modifying serves no useful purpose and should be dropped. Many medications provide incomplete or temporary suppression of inflammation, presumably by differing mechanisms of action. Based on this rationale, a therapeutic program is proposed, employing a combination of drugs to control inflammation in the critical early stages of RA. With this step-down bridge concept, medications are sequentially withdrawn in contrast to the traditional pyramid, in which they have been sequentially added. Our early experience with patients indicates that toxicity is no greater problem with combined drugs than with the same drugs used individually. Time and comparative observations will be needed to show the optimum combination of drugs and whether the step-down bridge concept will achieve the sought-for and presently unobtained goal of early and sustained control of inflammation, improved quality of life, and prevention of bone and joint damage.

Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease.

STUDY OBJECTIVE: To determine whether methotrexate has anti-inflammatory activity in refractory inflammatory bowel disease. DESIGN: Nonrandomized, open-label, preliminary trial of methotrexate along with standard medications for 12 weeks. SETTING: Referral-based gastroenterology practice. PATIENTS: Twenty-one patients with refractory inflammatory bowel disease (14, Crohn disease; 7, chronic ulcerative colitis); 17 taking variable doses of corticosteroids and 14 on sulfasalazine or metronidazole. Of the 21 patients, 10 had previously failed azathioprine or 6-mercaptopurine trials. INTERVENTIONS: Sulfasalazine and metronidazole were continued and prednisone dose was tapered according to clinical response. Methotrexate was given as a 25-mg intramuscular injection weekly for 12 weeks, then switched to a tapering oral dose if a clinical and objective improvement was noted. MEASUREMENTS AND MAIN RESULTS: Sixteen of twenty-one patients (11 of 14 patients with Crohn disease, 5 of 7 patients with chronic ulcerative colitis) had an objective response as measured by disease activity indices (modified Crohn's Disease Activity Index, 13.3 to 5.4 [P = 0.0001], Ulcerative Colitis Activity Index, 13.3 to 6.3 [P = 0.007]). Prednisone dosage decreased from 21.4 mg +/- 5.6 (SEM) to 5.5 mg +/- 2.0; P = 0.006 and 38.6 mg +/- 6.35 to 12.9 mg +/- 3.4; P = 0.01, respectively. Five patients with Crohn colitis had colonoscopic healing and 4 had normal histology at 12 weeks. In contrast, none of the 7 patients with ulcerative colitis had normal flexible sigmoidoscopies, despite histologic improvement in 5. Side effects included mild rises in transaminase levels in 2 patients, transient leukopenia in 1, self-limited diarrhea and nausea in 2 patients, and 1 case each of brittle nails and atypical pneumonitis. CONCLUSIONS: Although this pilot study is encouraging, further work is needed before methotrexate can be recommended for inflammatory bowel disease.

HLA genes associated with rheumatoid arthritis. Identification of susceptibility alleles using specific oligonucleotide probes.

We examined the association of individual HLA genes with rheumatoid arthritis (RA), using oligonucleotide probes that identified both DR4-associated and non-DR4-associated genes. Two distinct HLA-DR beta alleles (Dw4 and Dw14) were found in DR4+ RA patients compared with controls (Dw4 50% versus 17%; Dw14 35% versus 5%; total DR4 73% versus 30%), indicating that these 2 alleles are independent susceptibility genes. Remarkably, the majority of the DR4- RA patients also demonstrated a linear DNA sequence, apparently "shuffled" between different susceptibility alleles, identified with an oligonucleotide probe to a key portion of the Dw14 gene.

Identification of HLA-Dw14 genes in DR4+ rheumatoid arthritis.

Genes of the major histocompatibility complex, HLA, are associated with susceptibility to rheumatoid arthritis (RA), but the aetiology of this chronic inflammatory disease is not known. Synthetic oligonucleotide DNA probes were constructed to distinguish between two closely related but distinct alleles encoding the HLA-DR4 specificity in patients with RA. With these allele-specific oligonucleotide probes an uncommon DR4 genetic variant, Dw14, was identified in 6 of 7 RA patients homozygous for HLA-DR4. This allele may play an important part in susceptibility to RA.

Association between giant cell (temporal) arteritis and HLA-Cw3.

Thirty-five Caucasian patients with giant cell (temporal) arteritis were typed for HLA class I and II antigens. A significant increase was found for A31, B40, Cw3, and DR4. HLA-Cw3 was the most frequent antigen observed (57%) and had the highest relative risk (5.65), suggesting that Cw3 may be the primary HLA risk factor for this disease. The increased occurrence of A31, B40, and DR4 is probably secondary to their association with Cw3.

Polymyalgia rheumatica and giant cell arteritis. The dilemma of therapy.

Polymyalgia rheumatica, next to rheumatoid arthritis the most common inflammatory rheumatic disorder of the elderly, is a nonspecific clinical syndrome involving pain in the shoulder and pelvic girdles. Giant cell arteritis appears to localize in elastin-containing arteries and can cause similar myalgias. A relationship exists between the two diseases, as evidenced by their frequent coexistence in the same patient. The symptoms of polymyalgia rheumatica respond to low-dose corticosteroid therapy, while giant cell arteritis requires higher doses to prevent blindness due to involvement of the temporal artery. The key decision in therapy, therefore, concerns the dose and duration of use of steroid for polymyalgic symptoms. In this decision, prevention of the catastrophic complications of giant cell arteritis and avoidance of needless side effects of high-dose steroid therapy in the elderly are competing considerations.

Polymyalgia rheumatica and giant cell arteritis.

Polymyalgia rheumatica is a relatively common syndrome of older patients, mostly white, manifested by aching and morning stiffness of the pelvic and shoulder girdles and accompanied by a rapid erythrocyte sedimentation rate. The symptoms are due to a synovitis, which is mild, nondestructive and very responsive to low-dose steroid treatment, which may need to be continued for several years. Temporal arteritis, which may accompany polymyalgia, can present as headache, loss of vision, diplopia or jaw claudication. To suppress arterial inflammation and preserve vision, administration of prednisone, 50 mg a day for one month, is recommended, following which the dose is tapered according to the symptoms, not the sedimentation rate.