sign in sign up
<<
Home , Osteophyte

Is remission in rheumatoid associated with radiographic healing?

R. Rau

Department of Rheumatology, Evangel- ABSTRACT strong elevation of C-reactive protein isches Fachkrankenhaus Ratingen, The precondition for damage in (CRP) and erythrocyte sedimentation Ratingen, Germany. (RA) is inflamma- rate (ESR) are the best predictors of Rolf Rau, MD, PhD. tion, and the precondition for healing is progressive disease (1, 2). Therefore, Please address correspondence to: absence of inflammation. A systematic suppression of inflammation, generally Prof. Dr. med. Rolf Rau, Irisweg 5, search for healing phenomena in RA by disease-modifying antirheumatic D 40489 Düsseldorf, Germany. patients in remission has not yet been drugs (DMARDs), leads to slowing or E-mail: [email protected] undertaken. In reports of patients in halt of damage progression. Converse- Clin Exp Rheumatol 2006; 24 (Suppl. 43): whom healing was observed, clinical ly, groups of (3) or single joints S41-S44. and laboratory data have not been pub- (4) that never were swollen do not © Copyright CLINICAL AND EXPERIMENTAL lished in part due to space restrictions. develop erosions, and patients with per- RHEUMATOLOGY 2006. However, this preliminary review of the sistently low disease activity rarely get existing literature about repair sup- considerable joint damage. Key words: Radiographs, rheumatoid ports the thesis that a strong associa- A joint that has not been and is not arthritis, healing, remission. tion may exist between remission and affected by rheumatoid inflammation repair. Several reports indicate that therefore remains normal in its clinical patients in whom radiographic repair and radiographic appearance. A joint was seen were in clinical remission. In that had developed erosions during an most reports clinical response to treat- inflammatory phase of the disease but ment was very good, and in groups of becomes and remains inactive will – in patients in which scoring was done, the absence of inflammation – start a evidence of repair was seen in patients process of repair that can be detected with strong inhibition or halt of radio- on X-rays as soon as repair has reached graphic progression. In contrast, heal- a state that is visible radiographically. ing is unlikely to be detected in patients Repair is a completely normal process with persistent clinically active disease comparable to healing of a fracture. As and/or moderate or strong radiograph- the absence of inflammation is the pre- ic progression. condition for healing, the correlation between clinical remission and radio- No systematic investigations are avail- graphic repair should be strong. able yet to answer the question of Clinical experience and published data whether remission is associated with underscore this relationship (although radiographic healing in rheumatoid clinical and laboratory data frequently arthritis (RA). However, there are have not been published in case reports strong indications that radiographic due to space restrictions). healing occurs predominantly in pa- In the 11th edition of his textbook, pub- tients in remission or in a state of low lished in 1989, McCarty wrote: disease activity. This article is a brief and preliminary review of published Little has been written about healing of data indicating a relationship between erosions. In most instances, the bony control of disease activity and repair of cortex re-forms within the contour of a pocket erosion. This often accompanies joint damage. clinical remission, nearly always in- Many studies have documented that duced by a slow acting anti-rheumatic rheumatoid inflammation is the precon- drug. Occasionally, pocket erosions may dition and the main cause for joint dam- become filled-in with new (5). age in RA. As a rule, inflammatory dis- ease activity is well correlated with Already in 1982, McCarty and Carrera subsequent damage progression. Clini- (6) reported 17 patients with progres- cally very active disease as well as sive erosive seropositive RA refractory

S-41 RA remission and radiographic healing / R. Rau to conventional therapy, who had been signs of bone remodelling and osteo- “Substantial” clinical response was treated with a combination of cyclophos- phyte formation at MCP joints in the defined as > 50% improvement of both phamide, azathioprine, and hydroxy- “remission” films were seen that had swollen and tender joint counts and of chloroquine for an average of 27 not been present in their “activity” physician’s and patient’s assessment of months. Five patients achieved a com- films. Remodelling and osteophyte for- disease activity. A remission as defined plete remission, 2 had activity in a sin- mation are indicators of “secondary” by American College of Rheumatology gle joint only, 7 had partial disease sup- (OA) in joints in which (ACR) criteria (15) was not observed. pression, and 3 showed no response. inflammatory disease had been found Weisman included “healing of eros- Serial radiographs demonstrated previously. The presence of OA at the ions” and “reparative bone formation” recortication of erosions in 9 patients DIP joints did not correlate with the de- in her scoring system that was used in a with “filling-in” of some erosions in 3 velopment of osteophytes in the MCP 36-week trial of MTX versus aura- of these, no change in 5 patients, and joints. That means that the “primary” nofin. No differences regarding radio- progressive damage in 3. In this series, OA in the DIP joints is a different pro- graphic progression between the improvement (repair) occurred only in cess from the “secondary” OA seen in groups and no signs of repair were patients who had no radiographic pro- the MCP joints in these patients whose detected (16), likely because of the gression. RA had been controlled to remission. short duration of the trial. The majority The term “secondary osteoarthrosis” has We have demonstrated cases with heal- of patients in both groups had radio- been used in the European literature for ing of erosions since the early 1980s graphic progression. It is known from decades, and refers to degenerative and included images of such cases in other studies that in patients treated joint disease that develops secondary to reports on the inhibition of radiographic with conventional DMARDs the sec- injury of cartilage and bone due to progression with methotrexate (MTX) ond radiograph (taken after 6 or 12 inflammatory joint disease. This term (10), with parenteral gold (11, 12), or months) usually continues to indicate is based on the clear understanding of with both compounds (12). From that progression and that proof of radio- all clinicians that bony sclerosis and experience we concluded that “the pre- graphic progression inhibition can be osteophyte formation can occur only if condition for erosion healing seems to seen only after significant clinical res- the inflammatory process has come to be at least a sharp decrease in disease ponse has occurred. an end. Therefore, inactivation of RA, activity or a remission-like situation This view has been confirmed in a or “burnt out” RA, is a precondition for that lasts for several months”, since macro-radiographic study in 29 pa- the development of secondary degener- healing of erosion takes time. tients: 13 patients treated with paren- ative disease. Bony sclerosis and new In a series of 6 cases, 3 to 8 follow-up teral gold at presentation, 10 patients bone formation (i.e. osteophytes) are images of one joint each over periods treated with gold after a delay of 6 special features that indicate inactivity of 3 to 11 years (mean 7 years) were months, and 6 patients who received no of inflammation and repair at the same published, that demonstrated the gradu- gold at all (17). The computer-assisted time. (A joint with repair or degenera- al development from an active erosion calculation of the erosion area demon- tive changes is no longer actively to recortication, partial filling-in, com- strated an increase during the first half inflamed.) Interestingly, in his first plete filling-in, and restoration. In two year, no change during the second 6 publication concerning his scoring cases, the development of a secondary months, and a decrease in the erosion method (7), Sharp stated that “sclerosis osteoarthrosis was seen (13). All these area, indicating repair during the third and osteophytes were considered to be patients had responded very well to half year. This was true for gold-treated secondary changes” [in RA]. DMARD treatment and had reached a patients, while patients who were treat- As a special variant of the “usual” de- state of remission, near remission, or at ed only with nonsteroidal anti-inflam- velopment of secondary osteoarthrosis, least very low disease activity. matory drugs demonstrated continuous Dihlmann (8), as early as 1969, des- In a long-term trial of low dose MTX in progression. With gold, the number of cribed healing of erosions and remod- 26 patients, radiographs of and clinically “active joints” had decreased elling of joints without development of wrists obtained at baseline and after at from 6 to 2 during the first half year deformity as “arthritis reformans.” least 28 months of treatment were and to 1 after the second half year; the Cabral et al. (9) reviewed hand X-rays available in 14 patients. Five of these ESR decreased from 28 to 14 mm/h of 38 patients with RA whose disease patients had an improvement in the during the first half year and was 15 had gone into drug-induced remission number and size of erosions with evi- after 1 year, indicating that some of the for a mean duration of 2.5 years. Meta- dence of healing. The image of one pa- patients may have been in clinical re- carpophalangeal (MCP) joints and dis- tient’s hand demonstrated a subchon- mission (17). The study demonstrates tal interphalangeal (DIP) joints of good dral bone sclerosis, filling-in of an ero- clearly that clinical improvement with quality radiographs taken during active sion, and remodelling of bony surfaces. reduction in disease activity precedes disease and after a mean of 2.5 years in Three of the 5 patients with evidence of new bone formation with reduction of remission were scored according to the healing were among those 5 of 26 pa- erosion size indicating repair. method of Sharp (7); in addition, osteo- tients who exhibited the most “substan- A similar result was obtained by Men- phytes were identified. In 21 patients, tial” clinical response to MTX (14). ninger et al. (18) when investigating 27

S-42 RA remission and radiographic healing / R. Rau patients with early RA who participat- ic damage during clinically ineffective do not know when the last previous ed in a controlled trial of gold/MTX, in gold treatment and after switching radiograph had been taken, and it is which radiographs were scored accord- treatment to MTX. The change in med- likely that the erosion had developed ing to a modification of the Larsen sys- ication in these cases had been neces- before the patient went into remission. tem (19). A significant increase of the sary because of persistent clinically ac- But in rare occurrences, the inflamma- radiographic score indicating progres- tive disease and rapid radiographic pro- tory process may lead to a rarification sion was seen during the first half year, gression under gold treatment. After and weakening of the subchondral tra- a reduced progression rate during the switching to MTX, patients showed becular bone structure without an ap- second half year, and nearly no pro- significant improvement in disease ac- parent erosion, and the mechanical gression during the second and third tivity. Six of the 31 patients achieved breakdown of the cortical plate might year. In addition, the investigators sim- clinical remission according to Ameri- occur after the patient has achieved ply counted all joints that had im- can Association (ARA) clinical remission. To answer the ques- proved or progressed during the obser- criteria (15), and 12 patients had an tion of whether erosions also develop vation period. With time (radiographs ESR <15 mm/h. Serial radiographs of during clinical remission, radiographs had been taken at baseline and after 6, hands, wrists, and feet had been taken have to be taken as soon as the patient 12, 24, and 36 months), a significant after 1 to 5 years (mean 2.2 years) of has achieved remission and be repeated decrease in the number of deteriorating prior treatment and 2 to 6 years (mean 6 or 12 months thereafter. joints was found, along with an in- 3.9) after switching to MTX. The films A case report (22) describes a patient crease in the number of improving were scored using a modification of the who already had severe damage in sev- joints. Deterioration was defined as en- Larsen scoring system (19); in addi- eral joints when starting intramuscular largement and/or new development of tion, all joints were checked for the MTX treatment (15 mg/wk), which was erosions; improvement was defined as presence or absence of radiologic signs later switched to oral medication (20 recortication or filling-in of erosions. of active disease indicated as defined mg/wk) without folate supplementa- During the third year, the number of above. tion. After 1 year of treatment with MTX, joints with repair phenomena (9.3% of One figure in that report illustrates the she demonstrated clearly visible fill- joints) was greater than the number of change from an “active” to an “inac- ing-in of erosions, recortication, and joints that had deteriorated (7.1%) (18). tive” joint with sharply demarcated and densification of the bone structure in a (Active joints were defined as having sclerosed outline of the erosions, scle- number of different joints. Over the lesions with blurred outlines, indistinct rosis of the subchondral bone, and par- years, further improvement and remod- margins of erosions, and/or unsharp or tial filling-in of some erosions and elling of the joint structure toward re- diminished trabecular structure. Inac- cysts. Mean radiographic progression gaining normal function occurred. tive joints had to exhibit clear articular was significantly reduced during MTX Within 6 months, the ESR had im- outlines, have sharp demarcation of treatment when compared to the pre- proved from 39 mm/h to 25 mm/h and erosions and cysts, and normal trabecu- ceding gold treatment, accompanied by CRP from 4.1 mg/dL to 2.4 mg/dL. lar structure) (18). The number of “a sharp decrease in the proportion of After 1 year, the patient was in com- “active” joints increased significantly radiologically active joints,” from ap- plete remission with no joint swelling during the first 6 months and thereafter proximately 45% of all finger-, wrist-, or tenderness, normal mobility of all decreased continuously, while the num- and MTP joints at start of MTX treat- joints, ESR 19 mm/h, and CRP 0.5 ber of “inactive” joints increased con- ment to approximately 27% of all mg/dL. The patient remained in remis- tinuously after month 6. No clinical joints 2 years later. This observation sion after 4.5 years. In this case, clearly data were given (18), however, these implies that slowing of progression in visible repair could already be seen 1 27 patients were part of the study popu- the context of clinical improvement year after start of MTX treatment, at lation of a study comparing parenteral may be accompanied by “inactivation” the same time at which clinical remis- gold with parenteral MTX (20) in (in other words: healing) of radio- sion was observed. which approximately 35% of patients graphically “active” joints, as seen in A patient with very active disease who had achieved “clinical remission” (de- the study by Menninger (18). had failed to respond to parenteral fined as no swollen and tender joints, In two cases published by Sokka and gold, MTX, and sulfasalazine had ESR <20 mm/h in males and <30 mm/h Hannonen (21), erosion healing could severe radiographic progression in the in females, and no corticosteroids with- be documented on radiographs 2 and 4 forefeet, active disease with a CRP of in the last 4 weeks). The mean ESR had years after clinical remission; complete 4.3 mg/dL when starting anakinra (22). decreased to about 17 mm/h after 12 normalisation of the ESR had occurred She went into remission (ESR 10 and 36 months. Therefore, in this study, in these patients. In case 2, the patient mm/h, CRP <0.5 mg/dL) after 1 year, most of the patients in the cohort had a was in remission in January 1990 and 3 and at the same time, demonstrated state of low disease activity or even months later erosions were seen in recortication, new bone formation, and remission. proximal interphalangeal (PIP) joints. filling-in of small bone defects in the In a study including 31 RA patients, we This does not mean that erosions devel- interphalangeal joint of the left great documented progression of radiograph- op in spite of and during remission: we toe. Three years later, she demonstrated

S-43 RA remission and radiographic healing / R. Rau a remodelled joint with completely indicate that in cases with persistent sion in RA with parenteral gold treatment. restored proximal and distal joint sur- remission (small) damage progression 29th scientific meeting of the German Rheu- matology Association. Aachen; 2000. faces and a well-defined normal wide is quite unusual. It might occur only in 12. RAU R, HERBORN G, KARGER T et al.: A joint space while still treated with ana- those patients who still have some double-blind comparison of parenteral metho- kinra and still in clinical remission (22). active disease despite fulfilling existing trexate and parenteral gold in the treatment of Since healing phenomena had been remission criteria. The radiographs of early erosive rheumatoid arthritis. An interim report on 102 patients after 12 months. Sem detected only in sets of radiographs this study population would be ideal to Arthritis Rheum 1991; 21: 13-20. that were investigated with known time search for healing phenomena, since a 13. RAU R, HERBORN G: Healing phenomena of sequence of the films, we tried to number of radiographically “inactivat- erosive changes in rheumatoid arthritis answer the question of whether repair ed” joints – joints with signs of repair patients undergoing disease-modifying anti- rheumatic drug therapy. Arthritis Rheum could be identified also when radio- –should be detectable in patients with 1996; 39: 162-8. graphs were read in random order. For persistent remission. 14. WEINBLATT ME, TRENTHAM DE, FRASER PA this purpose, 24 sets of radiographs In conclusion, we can state that al- et al.: Long-term prospective trial of low- dose methotrexate in rheumatoid arthritis. containing healing phenomena were though a systematic study has not yet Arthritis Rheum 1988; 31: 167-75. mixed with 10 sets without healing and been undertaken, data from reports on 15. PINALS RS, MASI AT, LARSEN RA, AND THE read blinded and in random order. healing strongly indicate that remission SUBCOMMITTEE FOR CRITERIA OF REMISSION IN The group of patients with healing and radiographic repair are associated RHEUMATOID ARTHRITIS OF THE AMERICAN RHEUMATISM ASSOCIATION DIAGNOSTIC AND were found to have a slight mean phenomena. It is likely that in patients THERAPEUTIC CRITERIA COMMITTEE: Prelimi- decrease of the Ratingen score (24) in remission, healing phenomena can be nary criteria for clinical remission in rheuma- (indicating improvement) when all detected – and the presence of healing toid arthritis. Arthritis Rheum 1981; 24: joints of hands, wrists and feet were phenomena may indicate remission. 1308-15. 16. WEINBLATT ME, POLISSON R, BLOTNER SD scored. The group of patients without et al.: The effects of drug therapy on radio- healing demonstrated moderate pro- References graphic progression of rheumatoid arthritis: gression. Laboratory data have not 1. PLANT MJ, WILLIAMS AL, O’SULLIVAN MM, results of a 36-week randomized trial com- been published. However, since 13 of LEWIS PA, COLES EC, JESSOP JD: Relation- paring methotrexate and auranofin. Arthritis ship between time-integrated C-reactive pro- Rheum 1993; 36: 613-9. the 24 patients with healing had par- tein levels and radiologic progression in 17. BUCKLAND-WRIGHT JC, CLARKE GS, ticipated in the parenteral gold/par- patients with rheumatoid arthritis. Arthritis CHIKANZA IC, GRAHAME R: Quantitative enteral MTX study (20) with long-term Rheum 2000; 43: 1473-77. microfocal radiography detects changes in follow-up, their clinical data were easi- 2. VAN LEEUWEN MA, VAN RIJSWIJK MH, VAN erosion area in patients with early rheum- DER HEIJDE DMFM et al.: The acute-phase res- atoid arthritis treated with myocrisine. ly available. In 12 of these 13 patients, ponse in relation to radiographic progression J Rheumatol 1993; 20: 243-7. the ESR had decreased to values ≤20 in early rheumatoid arthritis: A prospective 18. MENNINGER H, MEIXNER C, SÖNDGEN W: mm/h; the mean value had decreased study during the first three years of the disease. Progression and repair in radiographs of Br J Rheumatol 1993; 32 (Suppl. 3): 9-13. from 34 mm/h to 10 mm/h. Eight hands and forefeet in early rheumatoid arthri- 3. VAN DER HEIDE A, REMME CA, HOFMAN DM, tis. J Rheumatol 1995; 22: 1048-54. patients had no tender joints, 5 had no JACOBS JWG, BIJLSMA JWJ: Prediction of 19. RAU R, HERBORN G: A modified version of swollen joints, and 4 had ≤2 swollen progression of radiologic damage in newly Larsen’s scoring method to assess radiologic joints. These data indicate that many of diagnosed rheumatoid arthritis. Arthritis changes in rheumatoid arthritis. J Rheumatol Rheum 1995; 38: 1466-74. 1995; 22: 1976-82. the patients with healing were in remis- 4. RAU R, HERBORN G, WASSENBERG S: 10 20. MENNINGER H, HERBORN G, SANDER O, sion or at least in a state of low disease year follow up data of the doubleblind study BLECHSCHMIDT J, RAU R: A 36 month com- activity. comparing parenteral gold and parenteral parative trial of methotrexate and gold sodi- Molenaar et al. (25) followed 187 pa- methotrexate in the treatment of rheumatoid um thiomalate in the treatment of early active arthritis: in preparation and erosive rheumatoid arthritis. Br J tients clinically and radiographically 5. MCCARTY DJ: Clinical picture of rheumatoid Rheumatol 1998; 37: 1060-8. for 2 years; these patients were in clini- arthritis. Arthritis and Allied Conditions. 21. SOKKA T, HANNONEN P: Healing of erosions cal remission according to a modifica- 1989: 732. in rheumatoid arthritis. Ann Rheum Dis 2000; tion (omitting fatigue) of the ACR cri- 6. MCCARTY DJ, CARRERA GF: Intractable rheu- 59: 647-9. matoid arthritis. JAMA 1982; 248: 1718-23. 22. WASSENBERG S, RAU R: Radiographic heal- teria (15). In patients with persistent 7. SHARP JT, LIDSKY MD, COLLINS LC, MORE- ing with sustained clinical remission in a remission (n = 93), they found a medi- LAND J: Methods of scoring the progression patient with rheumatoid arthritis receiving an increase of the radiographic score of radiologic changes in rheumatoid arthritis. methotrexate monotherapy. Arthritis Rheum Arthritis Rheum (Sharp/van der Heijde) of 0 and in pa- 1971; 14: 206-20. 2002; 46: 2804-7. 8. DIHLMANN W: On arthritis reformans. 23. RAU R, SANDER O, WASSENBERG S: Erosion tients with an exacerbation of RA (n = Fortschr Röntgenstr 1969; 111: 245-51. healing in rheumatoid arthritis after anakinra 86), a change score of + 1.0 (which is 9. CABRAL AR, LOYA BL, ALARCON-SEGOVIA treatment. Ann Rheum Dis 2003; 62: 671-3. less than 0.25% of the maximum D: Bone remodeling and osteophyte forma- 24. RAU R, WASSENBERG S, HERBORN G, STUC- tion after remission of rheumatoid arthritis. J KI G, GEBLER A: A new method of scoring score). In patients with persistent re- Rheumatol 1989; 16: 1421-27. radiographic change in rheumatoid arthritis. mission, clinically relevant progression 10. RAU R, HERBORN G, KARGER T, WERDIER J Rheumatol 1998; 25: 2094-107. (Sharp score increase >5 units/2 years) D: Retardation of radiologic progression in 25. MOLENAAR ETH, VOSKUYL AE, DINANT HJ, occurred in only 7% of patients com- rheumatoid arthritis with methotrexate thera- BEZEMER PD, BOERS M, DIJKMANS BAC: py: a controlled study. Arthritis Rheum 1991; Progression of radiologic damage in patients pared with 23% of patients who experi- 34: 1236-44. with rheumatoid arthritis in clinical remis- enced an exacerbation. These results 11. RAU R: Inhibition of radiographic progres- sion. Arthritis Rheum 2004; 50: 36-42.

S-44