The patients past medical history is significant for bleeding peptic ulcer 10 years prior and pleural tuberculosis that was successfully treated when she was in her twenties. Borderline hypertension (150/96) is another chronic health problem. Her family medical history is significant for moderate hypertension in both parents and two siblings. The patients mother has a history of osteoarthritis primarily involving the distal interphalangeal (DIP) joints.

 

Medications include lisinopril 10 mg/d. Although she had been prescribed a proton-pump inhibitor in the past, she is not currently utilizing this therapy. The patient admits taking occasional aspirin to relieve knee and foot pain on workdays.

 

Differential Diagnosis: On presentation, the patient complained of moderate fatigue and prolonged morning stiffness (All my muscles are thick.). Physical examination revealed moderate swelling with synovitis of the PIP and MCP joints of both hands, wrists, and symmetric involvement of both knees. PIP and MCP joints were tender to palpation with slight pain on motion. Some swelling of the metatarsophalangeal (MTP) joints was also noted.

 

The rest of the physical exam was normal, with no evidence of skin or mucous membrane lesions, nail lesions (pitting, onychodystrophy, or onycholysis), bowel complaints, or eye involvement. The systems review was also unremarkable and there was no history of photosensitivity or Raynauds phenomenon. With the exception of mild hypertension, the patients vital signs were within normal limits.

 

X-ray studies of the hands, wrists, and knees showed diffuse joint-space narrowing, with mild osteopenia in periarticular regions of the wrists. No erosions were seen. Soft tissue abnormalities noted on radiographs included periarticular swelling and joint effusion. Films of both feet showed early decalcification of the MTP joints. Chest X-ray was normal.
 
The diagnosis of rheumatoid arthritis (RA) should be considered in any patient with polyarticular inflammatory arthritis of greater than 6 weeks' duration, especially if the hands and feet are involved. The hallmark of the disease is a symmetric polyarthritis (synovitis) that typically affects the hands, feet, and wrists initially.

 

Significant fatigue may be present even in early RA. Joint distribution is critical in diagnosis. In the hands, the DIP joints are characteristically involved in osteoarthritis (OA), but seldom involved in RA; the PIP joints may be involved with either, whereas MCP involvement is the rule in RA and seldom occurs in OA.

 

The wrists are frequently involved in RA, whereas only the first carpometacarpal (CMC) joint is commonly involved in OA. MTP joint inflammation occurs in most RA patients, and is often one of the earliest disease manifestations.

 

RA may be difficult to differentiate from erosive inflammatory OA, however, the latter is mainly limited to the DIP and PIP joints of the hands. Other differential diagnoses include the seronegative spondylarthropathies (e.g., psoriatic arthritis, Reiter's syndrome).

 

Although psoriatic arthritis has a broad clinical pattern, the pattern of joint involvement is again of diagnostic value because the DIP joints (fingers and toes) are especially affected, and asymmetric involvement of large and small joints, including the spine, is common. Psoriasis antedates arthritis in most patients.

 

In Reiter's Syndrome, joint involvement generally is asymmetric and oligoarticular or polyarticular, occurring predominantly in the large joints of the lower extremities and in the toes. Typically, a triad of arthritis, conjunctivitis, and urethritis is present.

 

Pseudogout syndrome or chondrocalcinosis articularis may simulate OA when low-grade arthralgias result from the presence of calcium pyrophosphate dihydrate (CPPD) crystals in synovial fluid; the pattern of arthritis often involves wrists, knees, and hips.

 

The diagnosis of RA is a clinical one, based primarily on history and physical examination. No single finding is pathognomonic for RA. Therefore, a set of criteria were established by the American College of Rheumatology (ACR) and modified in 1988 for classification purposes.

 

The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the PIP, MCP, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. 

 

Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria. The new criteria have demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.

 

The patient's history and signs and symptoms, such as prolonged morning stiffness, soft tissue swelling, and symmetric radiographic involvement of PIP and MCP joints, supported a diagnosis of rheumatoid arthritis. Early demineralization in wrist X-rays was also consistent with a diagnosis of RA according to ACR criteria. On this basis, a tentative diagnosis of rheumatoid arthritis was made.

 

 Besides clinical features, laboratory parameters play an important role in diagnosis of rheumatoid arthritis. Imaging techniques provide another cornerstone in the diagnosis of RA.

 

According to ACR Subcommittee on Rheumatoid Arthritis Guidelines, baseline laboratory evaluations should include a complete blood count (CBC), including white blood cell differential and platelet counts, rheumatoid factor (RF) measurement, and measurement of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level.

 

Since the hands and feet are so frequently involved in RA, radiographs of these joints as well as other affected joints establish a baseline for future assessment of structural damage.

 

Although diffuse joint-space narrowing is commonly seen in other types of chronic inflammatory arthritis, in conjunction with marginal erosions and osteopenia, it is highly characteristic of RA. The initial changes may occur early in the course of the disease, especially in the hands, where studies show erosion in 20-50% of patients in the first 2 or 3 years.

 

Laboratory evaluations were performed and showed mild anemia (hematocrit 31% and hemoglobin 10.4 g/dL), with mild leukocytosis (10,500 mm3) and thrombocytosis (500,000 mm3). Laboratory findings were positive for serum RF. The titer of RF was high (1:100) and anti-nuclear antibody (ANA) titer was high normal (1:80). The patient's ESR was 35 mm/h, and assay for CRP was elevated.

 

As noted previously, X-ray studies of the hands, wrists, and knees showed diffuse joint-space narrowing. There was narrowing in PIP and MCP joints, with mild osteopenia in periarticular regions of the wrists, though without apparent erosions. Films of both feet also showed early demineralization of the MTP joints.

 

Presenting signs and symptoms, radiographic films, and laboratory parameters, were all consistent with a diagnosis of rheumatoid arthritis.  Laboratory evaluations were performed and showed mild anemia (hematocrit 31% and hemoglobin 10.4 g/dL), with mild leukocytosis (10,500 mm3) and thrombocytosis (500,000 mm3). Laboratory findings were positive for serum RF. The titer of RF was high (1:100) and anti-nuclear antibody (ANA) titer was high normal (1:80). The patient's ESR was 35 mm/h, and assay for CRP was elevated.

 

Presenting signs and symptoms, radiographic films, and laboratory parameters, were all consistent with a diagnosis of rheumatoid arthritis.  Poor prognosis is suggested by earlier age at onset, high titer of RF, elevated ESR, and swelling of more than 20 joints, functional disability within 1 year of onset, and persistently abnormal acute-phase reactants.

 

Studies of X-ray progression followed for 1-9 years have shown that 40-83% of subsequent progression can be predicted by a combination of prognostic factors such as joint involvement, high levels of CRP, and RF positivity. There are similar findings for predictors of functional disability in studies followed for 2-15 years. The most consistent prognostic feature is RF positivity, which is equally important in predicting joint damage and functional disability.

 

Studies have shown that patients with active polyarticular, RF-positive RA have greater than 70% probability of developing joint damage or erosions within 2 years of the onset of the disease. ESR is also correlated with disease activity and CRP level is correlated with radiographic evidence of disease progression.

 

The presence of ANAs has also been associated with more severe articular disease.  Extraarticular manifestations of RA, including rheumatoid nodules, Sjogren's syndrome, episcleritis and scleritis, interstitial lung disease, pericardial disease, systemic vasculitis, and Felty's syndrome, also indicate a worse prognosis.

 

While the ultimate goal of treating RA is to induce complete remission, this occurs infrequently. If complete remission is not achieved, the management goals are to control disease activity, alleviate pain, maintain function for activities of daily living and work, and maximize quality-of-life.

 

Achieving these goals requires determining the most efficacious combination of pharmacologic therapy, which may include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), low-dose prednisone, local injection of glucocorticoid, rehabilitation support, and analgesics.

 

Initial drug treatment usually involves salicylates, traditional nonselective NSAIDs, or cyclooxygenase-2 (COX-2) selective inhibitors because of their analgesic and anti-inflammatory properties.  Acetaminophen has inadequate inflammatory properties at typical doses. Aspirin is also a poor choice given the patient's history of bleeding ulcer. NSAID-induced gastropathy is also a well-recognized consequence of nonselective NSAID therapy in RA patients.

 

In fact, RA patients are nearly twice as likely as OA patients to have serious complications from NSAID treatment. Risk factors for the development of NSAID-related ulcers include history of ulcer, concomitant use of corticosteroids or anticoagulants, higher NSAID dose, use of multiple NSAIDs, serious underlying disease, or advanced age.

 

 The following approaches may be considered for RA patients who would benefit from an NSAID but who are at increased risk of serious adverse gastrointestinal (GI) effects: use of low-dose prednisone instead of an NSAID, use of a nonacetylated salicylate, use of a combination of a nonselective NSAID and gastroprotective agent, or use of a highly selective COX-2-specific inhibitor.

 

Two large outcome studies, CLASS and VIGOR, showed that patients receiving a COX-2-selective inhibitor experience significantly fewer clinically important upper GI events than patients taking nonselective NSAIDs.

 

Because the patient was at risk for an upper GI event, she was prescribed celecoxib 200 mg twice daily by her primary care physician to relieve pain and inflammation. She was instructed to discontinue taking aspirin.  The patient was referred to a rheumatologist for further evaluation. In addition, she was referred to a physical therapist who provided instruction in joint protection, conservation of energy, and instituted a home program of joint range of motion and strengthening exercises.

 

According to 2002 ACR Guidelines, joint examination alone may not adequately reflect disease activity; therefore, periodic measurements of ESR or CRP level and functional status, as well as radiographic examinations of involved joints should be performed. Functional status may be determined by questionnaires such as the Health Assessment Questionnaire (HAQ).

 

The American College of Rheumatology has also developed criteria for defining improvement and clinical remission. The ACR criteria for 20% clinical improvement (ACR-20) require 20% improvement in tender joint count and swollen joint count, as well as 20% improvement in three of the following parameters: patient global assessment, physician global assessment, patient assessment of pain, CRP levels, or HAQ score.

 

The patient continued to take celecoxib 200 mg twice daily with moderate relief of pain and swelling. However, she continued to be limited in activities of daily living, and physical examination by the rheumatologist several weeks later revealed tenderness of PIP and MCP joints of both hands, with flexor tendonitis of the palm that caused decreased range of motion of the fingers. Mild pain on motion and effusions were noted in both knees. There was also tenderness of MTP joints of both feet.

 

Review of x-rays revealed demineralization of the wrists, MCP and MTP joints, with some early subchondral erosions.  The work-up confirmed continued joint damage and persistent elevation of ESR and CRP level. The patient continued to complain of fatigue and noted that pain in her feet restricted her ability "to stand at the cash register and work." Because of ongoing disease activity and joint damage, the patient was placed on DMARD therapy.

 

The patient continued to take celecoxib 200 mg twice daily with moderate relief of pain and swelling. However, she continued to be limited in activities of daily living, and physical examination by the rheumatologist several weeks later revealed tenderness of PIP and MCP joints of both hands, with flexor tendonitis of the palm that caused decreased range of motion of the fingers. Mild pain on motion and effusions were noted in both knees. There was also tenderness of MTP joints of both feet.  Review of x-rays revealed demineralization of the wrists, MCP and MTP joints, with some early subchondral erosions.

 

The traditional "pyramid" or sequential approach to treatment involved use of an NSAID for months to years while seeking to avoid use of DMARDs until evidence of joint damage was seen. It was recommended that DMARDs be initiated only after there was radiographic evidence of disease activity.

 

However, most patients experienced poor long-term outcomes. While NSAIDs and glucocorticoids may alleviate RA symptoms, joint damage still continues to occur and progress even in the early months of the disease. In fact, the rate of erosions is greatest within the first 3 years of disease activity.

 

Since the goal of treatment is to intervene before joints are damaged, the 2002 ACR Guidelines recommend initiation of DMARD therapy not later than 3 months for any patient with an established diagnosis who, in spite of adequate treatment with NSAIDs, has ongoing joint pain, significant morning stiffness or fatigue, active synovitis, persistent elevation of the ESR or CRP level, or radiographic joint damage. For any untreated patient with persistent synovitis and joint damage, DMARD treatment should be started promptly to prevent or slow further damage.

 

The patient was placed on hydroxychloroquine 200 mg twice a day and instructed to continue to take celecoxib 200 mg twice daily. The physical therapy regimen was also maintained.

 

Conventional treatment with a single DMARD often fails to adequately control clinical symptoms or prevent disease progression. Consequently, combination DMARD therapy is an increasingly favored option, especially in patients (such as the one described here) who have "aggressive" disease from the onset.

 

Methotrexate is often used as the "anchor drug" in combination therapy. MTX as monotherapy or as a component of combination therapy should be instituted in patients whose treatment has not yet included MTX.

 

 Evidence from randomized, controlled clinical trials and observational studies have indicated increased efficacy and acceptable (often lower) toxicity for various combinations of MTX plus HCQ, SSZ, leflunomide, cyclosporine, etanercept, and infliximab. For example, a randomized controlled trial confirmed that the triple-DMARD combination of MTX, HCQ, and SSZ is more efficacious than MTX alone or HCQ plus SSZ.

 

The combination of MTX, HCQ, and SSZ has also been shown to be superior to double-DMARD combinations of MTX plus SSZ or MTX plus HCQ in both early and advanced RA. In another randomized controlled trial using a "step-down" approach, SSZ plus tapered doses of MTX and prednisolone in early RA was superior to SSZ alone.

 

Use of biologics is another option following suboptimal methotrexate response. Three TNF-alpha inhibitors are available in the US (etanercept, infliximab, and adalimumab); however, anti-TNF-alpha agents should be used with caution in patients with a history of tuberculosis.

 

Methotrexate was initiated at a dose of 7.5 mg per week. Routine CBC, creatinine, and liver function tests were scheduled monthly. However, after 6 weeks of therapy, the patient experienced a flare with prominent knee effusions particularly on the left side.

 

The methotrexate dose was increased from 7.5 to 10 mg per week and the patient received an intramuscular injection of triamcinolone acetonide 80 mg. Aspiration of the left knee excluded septic arthritis and an injection of intraarticular glucocorticoid was administered.

 

The patient experienced an improvement in symptoms and functional status, but after 6 months of follow-up, continued erosions were seen on hand and feet films. Physical examination revealed active synovitis of small joints of the hands, wrists, knees, and MTP joints. The patient continued to complain of fatigue and pain in her feet that limited her ability to work.

 

Methotrexate is frequently used as the first drug after antimalarials or sulfasalazine. It is also used as the first second-line therapy in patients with more active disease and functional disability. The drug has a rapid onset of action with clinical response occurring within 3 to 6 weeks after reaching a therapeutic dose.

 

The usual starting dose is 7.5 mg/wk and doses between 10 and 20 mg/wk are generally required for clinical response. For patients in whom response is not noted at oral doses of 20 mg/wk, the medication could be switched to parenteral administration to ensure better bioavailability. Higher doses of methotrexate may be required over time to maintain clinical response.

 

The patient was placed on an increased dose of methotrexate. Over the next 6 months she responded to therapy and the progression of disease was arrested. Serial laboratory evaluations revealed a decline in ESR that stabilized slightly outside the normal range. Her functional status also improved, but she continued to have some pain in her feet "after standing by the register for more than an hour." Examination revealed severe swelling of all the MTP joints, with associated tenderness and moderate deformities. The patient was scheduled for a surgical consultation.

 

According to the 2002 ACR Guidelines, surgical procedures should be considered in patients who have unacceptable levels of pain, loss of range of motion, and limitation of function because of structural joint damage. The most successful surgical procedures for RA are carpal tunnel release, synovectomy, resection of the metatarsal heads, total joint arthroplasty, and joint fusion.

 

Occupational and physical therapy expertise is an important component of restoring and optimizing function.

 

Slowing of radiographic progression has been documented with use of sulfasalazine, methotrexate, leflunomide, and TNF-alpha inhibitors.

 

Hydroxychloroquine alone does not slow radiologic damage.

 

 Adding a COX-2-specific inhibitor appears to increase the overall benefit in RA patients receiving ongoing treatment with DMARDs. COX-2 selective inhibitors and traditional NSAIDs have similar efficacy in RA, but COX-2-specific inhibitors have a superior GI safety profile. Cyclooxygenase plays an important role in both peripheral and central sensitization.

 

In the peripheral nervous system, for example, COX-2 is induced following inflammation and acts on arachidonic acid to cause an increase in prostaglandins. In turn, prostaglandins increase the sensitivity of peripheral nociceptors by making the nociceptor terminals more responsive to stimuli.

 

Because prostaglandins appear essential for the development and persistence of hyperalgesia, COX-2 might play an important role in the development of sensitization and chronic pain.